Intermediates for urea and thiourea derivatives

ABSTRACT

This invention relates to amine derivatives and salts thereof. These compounds have an anti-ulcer activity which is effective to human beings and animals. This disclosure relates to such compounds, a process for the preparation thereof and an anti-ulcer agent containing the same.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to a novel amine derivative, a salt thereof, aprocess for preparing the same and an anti-ulcer agent containing thesame.

The compounds of this invention have excellent inhibitory activity ongastric acid secretion, anti-ulcer activity and improving activity ofgastric mucosal blood flow. They have a long duration of the activityand exhibit the effects at a low dose. Therefore safety margins of themare very wide.

It has heretofore been known that compounds having a histamine H₂-blocking effect are useful for treating peptic ulcer. The presentinventors have devoted themselves to research on compounds which block ahistamine H₂ receptor, and have consequently found that aminederivatives represented by the hereinafter described general formula (I)and salts thereof have an excellent anti-ulcer activity.

SUMMARY OF THE INVENTION

The compounds of this invention have the formula (I) ##STR1## arecharacterized by having ##STR2## in the molecule.

An object of this invention is to provide a novel amine derivativehaving ##STR3## in the molecule and a salt thereof.

Another object of this invention is to provide a novel amine derivativeand a salt thereof which have an anti-ulcer activity.

A further object of this invention is to provide a process for producinga novel amine derivative or a salt thereof.

A still further object of this invention is to provide a pharmaceuticalcomposition containing a novel amine derivative or a salt thereof as anactive ingredient.

A still further object of this invention is to provide a method fortreating peptic ulcer.

Other objects and advantages of this invention will become apparent fromthe following description.

The compounds of this invention are amine derivatives represented by thefollowing formula (I) and salts thereof: ##STR4## wherein each of R¹ andR², which may be the same or different, is a substituted orunsubstituted aryl or heterocyclic group; p is 0, 1, 2 or 3; X is anoxygen or sulfur atom; q is 2, 3 or 4; Z is an oxygen or sulfur atom,NR⁴ (R⁴ is a hydrogen atom, a cyano group, a hydroxyl group, a nitrogroup, an alkyl group, an alkenyl group, an alkoxy group, a substitutedor unsubstituted acyl group, a substituted or unsubstituted aryl group,a carbamoyl group, a sulfamoyl group, an alkoxycarbonyl group, analkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group,a substituted or unsubstituted aryloxy group, a substituted orunsubstituted acylamino group, an alkoxycarbonylamino group, or acarboxyalkylamino group), or CHR⁵ (R⁵ is a nitro group, a substituted orunsubstituted acyl group, a substituted or unsubstituted aryl group, analkylsulfonyl group or a substituted or unsubstituted arylsulfonylgroup); Y is an alkylene group, and R³ is a hydrogen atom or ahydroxyl-protecting group.

In the present specification, unless otherwise specified, the term"alkyl group" means a C₁₋₈ alkyl group such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, octyl or thelike; the term "alkenyl group" means a C₂₋₄ alkenyl group such as vinyl,allyl, isopropenyl, butenyl or the like; the term "cycloalkyl group"means a C₃₋₇ cycloalkyl group such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or the like; the term "alkoxygroup" means a C₁₋₄ alkoxy group such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy or the like; the term "alkenyloxy group" means aC₂₋₄ alkenyloxy group such as vinyloxy, allyloxy, isopropenyloxy,butenyloxy or the like; the term "alkylthio group" means a C₁₋₄alkylthio group such as methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio or the like; the term "alkylsulfinyl group"means a C₁₋₄ alkylsulfinyl group such as methylsulfinyl, ethylsulfinylor the like; the term "hydroxyalkyl group" means a hydroxy-C₁₋₄ alkylgroup such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl or the like; the term "alkoxyalkylgroup" means a C₁₋₄ alkoxy-C₁₋₄ alkyl group such as methoxymethyl,ethoxymethyl, 2-methoxyethyl, 3-methoxypropyl or the like; the term"halogenoalkyl group" means a halogeno-C₁₋₄ -alkyl group such aschloromethyl, bromomethyl, dichloromethyl, dibromomethyl,trifluoromethyl or the like; the term "alkylamino group" means a C₁₋₄alkylamino group such as methylamino, ethylamino, n-propylamino,n-butylamino or the like; the term "dialkylamino group" means a di-C₁₋₄alkylamino group such as dimethylamino, ethylmethylamino, diethylamino,di-n-butylamino or the like; the term "acyl group" means a formyl group,a C₂₋₅ -alkanoyl group such as acetyl, propionyl, isovaleryl, pivaloylor the like, a C₅₋₈ cycloalkanecarbonyl group such ascyclopentylcarbonyl, cyclohexylcarbonyl or the like, an aroyl group suchas benzoyl, toluoyl, 2-naphthoyl or the like, and a heterocycliccarbonyl group such as 2-thenoyl, 3-furoyl, nicotinoyl or the like; theterm "acyloxy group" means the above-mentioned acyl group bonded to anoxygen atom; the term "aryl group" means a group derived from anaromatic hydrocarbon such as phenyl, naphthyl, indanyl or the like; theterm "aralkyl group" means an ar-C₁₋₄ alkyl group such as benzyl,phenethyl, naphthylmethyl or the like; the term "acyloxyalkyl group"means the above-mentioned acyl group bonded to the above-mentionedhydroxyalkyl group; the term "carbamoyl group" means NH₂ CO--, a C₁₋₄alkylaminocarbonyl group such as methylaminocarbonyl,ethylaminocarbonyl, propylaminocarbonyl or the like, and a di-C₁₋₄alkylaminocarbonyl group such as dimethylaminocarbonyl,diethylaminocarbonyl or the like; the term "sulfamoyl group" means NH₂SO₂ --, a C₁₋₄ alkylaminosulfonyl group such as methylaminosulfonyl,ethylaminosulfonyl, propylaminosulfonyl or the like, and a di-C₁₋₄alkylaminosulfonyl group such as dimethylaminosulfonyl,diethylaminosulfonyl or the like; the term "alkylsulfonyl group" means aC₁₋₄ alkylsulfonyl group such as methanesulfonyl, ethanesulfonyl or thelike; the term "arylsulfonyl group" means an arylsulfonyl group such asbenzenesulfonyl, naphthalenesulfonyl or the like; the term "acylaminogroup" means an acylamino group in which the acyl group is the same asmentioned above; the term "aryloxy group" means phenyloxy, naphthyloxyor the like; and the term "halogen atom" means fluoro, chloro, bromo,iodo, or the like.

Each of R¹ and R² in the general formula (I), which may be the same ordifferent, represents a substituted or unsubstituted aryl or heterocylicgroup, and the heterocyclic group includes, for example, heterocyclicgroups containing at least one hetero atom selected from nitrogen,sulfur and oxygen atoms in the ring such as thienyl, furyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,thiazolidinyl, oxazolidinyl, 1,3,4-thiadiazolyl, 1,2,4-triazolyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl,benzothienyl, benzoimidazolyl, 1,4-benzodioxanyl and the like. The aryland heterocyclic groups for R¹ and R² may be substituted by at least onesubstituent such as a halogen atom; a hydroxyl group; a nitro group; anoxo group; a cyano group; a carboxyl group; a carbamoyl group; amercapto group; an amino group; an alkyl group; an alkenyl group; analkoxy group; an alkylthio group; an alkylsulfinyl group; analkylsulfonyl group; an alkylthioalkyl group such as methylthiomethyl,ethylthiomethyl, methylthioethyl or the like; a S-oxide derivative ofthe alkylthioalkyl group; a hydroxyalkyl group; an alkenyloxy group; analkoxyalkyl group; a hydroxyalkyloxy group such as 2-hydroxyethoxy,3-hydroxypropoxy or the like; a halogenoalkyl group; an alkylaminogroup; a dialkylamino group; an acyl group; an acyloxy group; anacyloxyalkyl group; an alkylenedioxy group such as methylenedioxy,ethylenedioxy, trimethylenedioxy or the like to be linked to theadjacent carbon atoms in the aryl or heterocyclic group; a cycloalkylgroup; an aryl group; an aralkyl group; an acylamino group; the formula##STR5## (R⁶ and R⁷, which may be the same or different, representhydrogen atoms, alkyl groups, cycloalkyl groups, alkenyl groups, aralkylgroups, hydroxyl groups, halogenoalkyl groups, hydroxyalkyl groups,alkoxyalkyl groups, amino-C₁₋₄ alkyl groups such as 2-aminoethyl,3-aminopropyl or the like, C₁₋₄ alkylamino-C₁₋₄ alkyl groups such asmethylaminomethyl, 2-methylaminoethyl or the like, or di-C₁₋₄alkylamino-C₁₋₄ alkyl groups such as dimethylaminomethyl,2-dimethylaminoethyl or the like, or R⁶ and R⁷, when taken with thenitrogen atom to which they are bonded, form a saturated heterocyclicgroup; and A is an alkylene group such as methylene, ethylene,propylene, trimethylene, tetramethylene or the like), or the formula##STR6## (R⁸ is a hydrogen atom, an alkyl group, a halogenoalkyl groupor an acyl group).

Among these substituents, the saturated heterocyclic group which R⁶ andR⁷ form when taken with the nitrogen atom to which they are bonded,includes, for example, nitrogen-containing saturated heterocyclic groupswhich may further contain a hetero atom selected from nitrogen, sulfurand oxygen atoms in the ring such as 1-pyrrolidinyl, piperidino,morpholino, thiomorpholino, 1-hexamethyleneimino, 1-piperazinyl,4-methyl-1-piperazinyl, 3-hydroxy-1-pyrrolidinyl,3-hydroxymethyl-1-pyrrolidinyl, 2-hydroxymethyl-1-pyrrolidinyl,3-hydroxy-1-piperidinyl, 4-hydroxy-1-piperidinyl,3-hydroxymethyl-1-piperidinyl, 4-hydroxymethyl-1-piperidinyl and thelike.

Z represents an oxygen atom, a sulfur atom, NR⁴ or CHR⁵, in which R⁴represents a hydrogen atom; a cyano group; a hydroxyl group; a nitrogroup; an alkyl group; an alkenyl group; an alkoxy group; a substitutedor unsubstituted acyl group; a substituted or unsubstituted aryl group;a carbamoyl group; a sulfamoyl group; an alkoxycarbonyl group, forexample, a C₁₋₄ alkoxycarbonyl group such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl or the like; an alkylsulfonyl group; asubstituted or unsubstituted arylsulfonyl group; a substituted orunsubstituted aryloxy group; a substituted or unsubstituted acylaminogroup; an alkoxycarbonylamino group, for example, a C₁₋₄alkoxycarbonylamino group such as methoxycarbonylamino,ethoxycarbonylamino, n-butoxycarbonylamino or the like; acarboxyalkylamino group, for example, a carboxy-C₁₋₄ alkylamino groupsuch as carboxymethylamino, 2-carboxyethylamino or the like, and R⁵represents a nitro group, a substituted or unsubstituted acyl group; asubstituted or unsubstituted aryl group; an alkylsulfonyl group or asubstituted or unsubstituted arylsulfonyl group.

The substituents for R⁴ and R⁵ include alkyl groups, halogenoalkylgroups, alkoxy groups, halogen atoms and the like.

Y is an alkylene group, which includes, for example, C₁₋₄ alkylenegroups such as methylene, ethylene, propylene, trimethylene,tetramethylene and the like.

R³ represents a hydrogen atom or a hydroxyl-protecting group. Thehydroxyl-protecting group includes, for example, acyl groups; asubstituted or unsubstituted alkoxycarbonyl groups such as1,1-dimethylpropoxycarbonyl, tert.-butoxycarbonyl, isopropoxycarbonyl,2,2,2-trichloroethoxycarbonyl, ethoxycarbonyl,2,2,2-tribromoethoxycarbonyl and the like; a substituted orunsubstituted aralkyloxycarbonyl groups such as benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)-benzyloxycarbonyland the like; halogenoalkanoyl groups such as monochloroacetyl,trifluoroacetyl and the like; 2-furfuryloxycarbonyl group;1-adamantyloxycarbonyl group; 8-quinolyloxycarbonyl group; benzyl group;diphenylmethyl group; trityl group; alkyl groups; methoxymethyl group;tetrahydrofuryl group; tetrahydropyranyl group; 2-nitrophenylthio group;2,4-dinitrophenylthio group; organic silyl-containing groups such astrimethylsilyl, tert.-butyldimethylsilyl and the like; etc.

The salts of the compound represented by the general formula (I)include, for example, salts with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid and the like;salts with organic acids such as acetic acid, propionic acid, oxalicacid, citric acid, lactic acid, maleic acid, succinic acid, tartaricacid, mandelic acid, p-toluenesulfonic acid, picric acid, sulfamic acidand the like; salts with alkali metals such as sodium, potassium and thelike; salts with alkaline earth metals such as calcium, magnesium andthe like; and salts with nitrogen-containing organic bases such asprocaine, N-benzyl-β-phenethylamine, 1-ephenamine,N,N-dibenzylethylenediamine, triethylemine, N-methylpiperidine and thelike.

The amine derivatives of the general formula (I) and their salts of thisinvention include their isomers such as geometrical isomers, tautomers,optical isomers, and racemic isomers, and further include all of theircrystal forms and hydrates.

Preferable compounds among the above-mentioned amine derivatives of thegeneral formula (I) and their salts of this invention are, for example,compounds in which R¹ and R² are independently groups selected fromsubstituted or unsubstituted phenyl, indanyl, thienyl, furyl, pyridyl,thiazolyl and imidazolyl groups and compounds in which Z is an oxygenatom, a nitromethylene group, an alkylsulfonylimino group, or asubstituted or unsubstituted arylsulfonylimino group, a cyanoiminogroup, or a sulfamoylimino group.

More preferably, there are exemplified compounds represented by thefollowing formulas (Ia), (Ib) and (Ic) and salts thereof: ##STR7##wherein R⁹ is a hydrogen atom or an alkyl group, and R², R³, R⁶, R⁷, A,p, q, X, Y and Z have the same meanings as defined above, ##STR8##wherein R², R³, R⁶, R⁷, R⁹, A, p, q, X, Y and Z have the same meaningsas defined above, ##STR9## wherein R², R³, R⁶, R⁷, A, q, X, Y and Z havethe same meanings as defined above.

Among these compounds of the formulas (Ia) to (Ic), more preferable arethose compounds in which R⁶ and R⁷ are independently alkyl groups, or R⁶and R⁷ form a saturated heterocyclic group when taken with the nitrogenatom to which they are bonded; those compounds in which p is 1 and q is2 or 3; those compounds in which Z is NR^(4a) (R^(4a) is a cyano groupor an alkylsulfonyl group) or a nitromethylene group (CHNO₂); and thosecompounds in which Y is methylene and R² is a substituted orunsubstituted phenyl, indanyl, thienyl, furyl or pyridyl group.

According to this invention, there can be obtained a highly safecompound which exhibits an excellent inhibitory activity on gastric acidsecretion, an excellent anti-ulcer activity and improving activity ofgastric mucosal blood flow when administered orally or parenterally, andretains these activities for a long time.

Next, the pharmacological effects of typical compounds of the aminederivative of the formula (I) and the salt thereof are described below.

[I] Inhibitory effect on gastric acid secretion

(i) Perfused stomach preparation of anesthetized rat [according to M. N.Ghosh and H. O. Schild: Brit. J. Pharmacol. 13, 54 (1958)]

Wistar strain rats (male, 200 to 250 g) starved for 18 hours wereanesthetized with urethane and then subjected to laparotomy, after whichthe forestomach region of the stomach of each rat was incised. The wholeinterior of the stomach was sufficiently washed with physiologicalsaline, and the cut edges were sutured. A silicone tube was insertedinto the stomach to a length of about 5 mm from the duodenum side andfixed. Subsequently, the stomach was perfused with physiological salineadjusted to a pH of about 10 with an aqueous sodium hydroxide solutionat a constant rate (1 ml/min) through an oral sonde, and the change inpH of the perfusate which had flowed out through the silicone tube wascontinuously recorded. During the perfusion, histamine (30 μg/kg/min)was continuously injected, as an agent for stimulating gastric acidsecretion, through the femoral vein at a rate of 0.3 ml/min. Each drugwas intravenously administered when the acid secretion became almostconstant (pH 3.3±0.2), and cumulatively administered when the inhibitionof acid secretion at each dose reached a plateau.

A period from the time at which the acid secretion was almost completelyinhibited by the cumulative administration of the drug and the pH of theperfusate which had flowed out became about the same as that before thehistamine administration to the time at which the pH became 4 wasdefined as duration of the activity. The number of experiments was threefor each dose.

The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Drug         Dose for complete                                                                           Duration                                           No.          inhibition (mg/kg)                                                                          (min)                                              ______________________________________                                         1           0.30          >210                                                2           0.10          >160                                                3           0.10          155                                                 4           0.04          220                                                 5           0.10          192                                                 6           0.10          132                                                 7           0.10          227                                                 8           0.30          200                                                 9           0.20          190                                                10           0.18          175                                                11           0.05          123                                                12           0.15          >240                                               13           0.10          >240                                               14           0.15          158                                                15           0.06          180                                                16           0.10          304                                                17           0.15          >280                                               18           0.30          247                                                19           0.10          164                                                20           0.20          >210                                               21           0.10          >240                                               22           0.04          136                                                23           0.15          242                                                24           0.20          >240                                               25           0.10          >240                                               26           0.30          >240                                               27           0.30          >210                                               28           0.10          205                                                29           0.30          >177                                               30           0.15          >240                                               31           0.30          226                                                32           0.30          >220                                               33           0.30          >240                                               Cimetidine   3.00           16                                                Ranitidine   0.50           92                                                ______________________________________                                    

Drugs

1.N-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N"-(β-hydroxyphenethyl)guanidine

2.N-{2-[(2-guanidino-4-thiazolyl)methylthio]-ethyl}-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine

3.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-2-nitro-1,1-ethenediamine

4.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-(2-fluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

5.N-[2-(4-chlorophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

6.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-hydroxy-2-(2-thienyl)ethyl]-2-nitro-1,1-ethenediamine

7.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methyl-2-thienyl)ethyl]-2-nitro-1,1-ethenediamine

8.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-pyridyl)ethyl]-2-nitro-1,1-ethenediamine

9.N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediamine

10.N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-2-nitro-1,1-ethenediamine

11.N-(β-hydroxyphenethyl)-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

12.N-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

13.N-[2-hydroxy-2-(3-hydroxyphenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

14.N-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

15.N-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

16.N-[2-(4-chlorophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

17.N-[2-hydroxy-2-(3,4-methylenedioxyphenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

18.N-[2-hydroxy-2-(3-methyl-2-thienyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

19.N-[2-hydroxy-2-(3-pyridyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

20.N-[2-hydroxy-2-(4-nitrophenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

21.N-(β-hydroxyphenethyl)-N'-methanesulfonyl-N"-[3-(3-piperidinomethylphenoxy)propyl]guanidine

22.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[S(+)-2-hydroxy-2-(4-hydroxyphenyl)ethyl]-2-nitro-1,1-ethenediamine

23.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediamine

24.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-hydroxy-2-(4-methylthiophenyl)ethyl]-2-nitro-1,1-ethenediamine

25.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-(3,4-difluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

26.N-[2-hydroxy-2-(4-methylthiophenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

27.N-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

28.N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

29.N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methylphenyl)ethyl]-2-nitro-1,1-ethenediamine

30.N-[2-(3,4-difluorophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

31.N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(3-ethylphenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

32.N-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

33.N-{2-[[-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-2-nitro-1,1-ethenediamine

Cimetidine:1-Cyano-2-methyl-3-{2-[(5-methyl-4-imidazolyl)methylthio]ethyl}guanidine

Ranitidine:N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-methyl-2-nitro-1,1-ethenediamine

(ii) Pylorus ligation method [according to H. Shay et al:Gastroenterology, 5, 43 (1945)]

Five to six Wistar strain rats (male, 190 to 230 g) per group werestarved for 35 hours, after which each drug was orally administered, andafter 2 hours, the pylorus of each rat was ligated under etheranesthesia. Subsequently, the abdominal wall was sutured, immediatelyafter which histamine was administered subcutaneously on the back at adose of 25 mg/kg. After 3 hours, each rat was killed, after which thecardiac portion was ligated, and the was removed. After 1 ml ofdistilled water was injected into the stomach, the gastric juice wascollected by centrifugation and its volume was measured. The acidity ofthe gastric juice was measured by titrating 1 ml of the gastric juicewith a 0.1N aqueous sodium hydroxide solution, taking pH 7.0 as theend-point. Physiological saline was administered to a control group.

The inhibition percentage of gastric acid secretion was determined fromthe following equation: ##EQU1##

The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                                Inhibition                                            Drug No.     Dose (mg/kg)                                                                             percentage (%)                                        ______________________________________                                         3           3           82**                                                              1          75*                                                    4           3           75**                                                  5           3          80*                                                    6           10          93**                                                              3          67*                                                    7           3          88*                                                    9           1          75*                                                   11           10          81**                                                              3           79**                                                 12           3           87**                                                 13           1          51*                                                   14           1          61*                                                   15           1          77*                                                   16           3          89*                                                   17           3           70**                                                 18           3           87**                                                 29           1          56*                                                   32           1.5        60*                                                   33           1           55**                                                 34           3          71*                                                   35           1          47*                                                   36           3          85*                                                   37           3          77*                                                   38           1          41*                                                   39           3           90**                                                 40           10          85**                                                              3          75*                                                   41           1          65*                                                   42           1          57*                                                   43           1          51*                                                   44           1          75*                                                   45           1           65**                                                 Cimetidine   90          97**                                                              30         60*                                                                10         39                                                    Ranitidine   30          91**                                                              10         56*                                                                3          17                                                    ______________________________________                                         Note:-                                                                        *p < 0.05                                                                     **p < 0.01                                                               

Drugs

34.N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(2,6-difluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

35.N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(2,4-difluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

36.N-[2-(2-fluorophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

37.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-hydroxy-2-(4-methoxyphenyl)-ethyl]-2-nitro-1,1-ethenediamine

38.N-{2-[[5-(dimethylamino)methyl-2-furyl]-methylthio]ethyl}-N'-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

39.N-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-hydroxy-2-(2-methylphenyl)ethyl]-2-nitro-1,1-ethenediamine

40.N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-(.beta.-hydroxyphenethyl)-2-nitro-1,1-ethenediamine

41.N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

42.N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(4-ethylphenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

43.N-[2-(3-fluorophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

44.N-[2-hydroxy-2-(2-methylphenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

45.N-[2-(4-aminophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine

[II] Effect on isolated guinea pig atrium

Hartley guinea pig (male, 300 to 400 g) was killed by blood-letting,immediately after which the heart was isolated, and the right atrium wasseparated in a Krebs-Henseleit solution and used as a preparation. Thepreparation was suspended (load: 1 g) in a Magnus tube containingKrebs-Henseleit solution (30° C.) through which a mixed gas of 95% of O₂and 5% of CO₂ had been bubbled, and its motion was isometricallyrecorded on polygraph. The preparation was trained in a bath fluid, andafter the heart rate became constant, 5×10⁻⁶ M of histamine wasadministered. After the heart rate became constant, each drug wasadministered cumulatively.

The inhibition percentage was determined from the following equation:##EQU2## HR_(min) : heart rate before the administration of histamineHR_(max) : heart rate after the administration of histamine

HR_(x) : heart rate at the time of the administration of each drug.

The doses and the inhibition percentages were plotted on a logarithmicprobability paper, and the 50% inhibition dose (ID₅₀) was determined.The number of experiments were five for each dose.

The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Drug No.     ID.sub.50 (M)                                                                             Potency ratio                                        ______________________________________                                         3           2.28 × 10.sup.-7                                                                    14.7                                                  4           2.25 × 10.sup.-7                                                                    14.9                                                  9           2.45 × 10.sup.-7                                                                    13.7                                                 15           2.18 × 10.sup.-7                                                                    15.4                                                 17           2.18 × 10.sup.-7                                                                    15.4                                                 42           2.37 × 10.sup.-7                                                                    14.1                                                 Cimetidine   3.35 × 10.sup.-6                                                                    1                                                    ______________________________________                                    

[III] Anti-ulcer activity

(i) Indomethacin ulcer

Six Wistar strain rats (male, 200 to 250 g) per group were starved for24 hours, after which each drug was orally administered, and after 30minutes, Indomethacin was injected subcutaneously at a dose of 30 mg/kg.After 5 hours, each rat was killed, and the stomach was removed andfixed with 3% formalin, after which the lengths of ulcers formed in thestomach was measured under the binocular stereoscopic microscope (10×),and the sum total of the lengths was taken as the ulcer index. To acontrol group was administered 0.5% Tween 80 physiological saline. Theinhibition percentage was determined from the following equation:##EQU3##

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                                Dose      Inhibition  ID.sub.50                                                                             Potency                                 Drug No.                                                                              (mg/kg)   percentage (%)                                                                            (mg/kg) ratio                                   ______________________________________                                        3       10        71*         3.40    8.1                                             3         51*                                                                 1         20                                                          9       10        97**        0.70    39.3                                            3         85**                                                                1         70**                                                                0.3       6                                                           15      10        98**        0.40    68.8                                            3         92**                                                                1         88**                                                                0.3       37                                                          29      1         57*         0.88    31.3                                            0.3       8                                                           32      3         72*         1.81    15.2                                            1         24                                                          40      3         82*         1.30    21.2                                            1         40                                                          Cimetidine                                                                            100       97**        27.5    1                                               30        50                                                                  10        18                                                          Ranitidine                                                                            30        98**        15.5    1.8                                             10        18                                                          ______________________________________                                         Note:-                                                                        *p < 0.05                                                                     **p < 0.01                                                               

(ii) Mepirizole-induced duodenal ulcer

A test was carried out according to the method of Okabe et al. [S. Okabeet al., Gastroenterology, 80, 1241 (1981)].

Six Wistar strain rats (male, 200 to 250 g) per group were starved for24 hours, after which each drug was orally administered, and after 30minutes, mepirizole was injected subcutaneously at a dose of 200 mg/kg.After 18 hours, the stomach and duodenum were removed and fixed with 3%formalin, after which the areas and depths of the ulcers formed in theduodenum were measured under the binocular stereoscopic microscope(10×). The scores were given in 7 grades depending on the areas anddepths of the ulcers, and the sum total of the scores was taken as theulcer index. The scores were given as follows:

That is to say, the score is 0 at an ulcer area of 0 to 0.2 mm², 1 at0.2 to 1.0 mm², 2 at 1 to 3 mm², 3 at 3 to 6 mm², 4 at 6 to 10 mm², and5 at 10 mm² or more, the ulcer in the condition immediately beforeperforation is scored as 6, and the ulcer which had caused perforationis scored as 7.

To a control group was administered 0.5% Tween 80 physiological saline.The inhibition percentage was determined from the following equation:##EQU4##

The results are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                                Dose      Inhibition  ID.sub.50                                                                             Potency                                 Drug No.                                                                              (mg/kg)   percentage (%)                                                                            (mg/kg) ratio                                   ______________________________________                                        3        10       97**        2.9     55.9                                             3        49**                                                                 1        12                                                          9        10       93**        4.3     37.7                                             3        33*                                                                  1        -8                                                          15       10       93**        4.5     36.0                                             3        29*                                                                  1        2                                                           Cimetidine                                                                            .sup. 300.sup.a                                                                         59*         162     1                                               .sup. 100.sup.b                                                                         43*                                                         Ranitidine                                                                            100       78**        32      5.1                                              30       49*         32      5.1                                     ______________________________________                                         Note:-                                                                        .sup.a Four of six rats died.                                                 .sup.b Two of six rats died.                                                  *p < 0.05                                                                     **p < 0.01                                                               

(iii) Stress ulcer induced by water-immersion

An experiment was carried out according to the method of Takagi et al.[K. Takagi et al., Jap. J. Pharmacol., 18, 9 (1968)].

Six Wistar strain rats (male, 230 to 280 g) per group were starved for24 hours, after which each drug was orally administered. After 30minutes, the rats were placed in stress cage, immersed in water at 23°C. to the dpeth of xiphoid, and allowed to stand therein for 15 hours.Thereafter, the stomach of each rat was removed and then fixed with 3%formalin, after which the areas of the ulcers formed were measured underthe binocular stereoscopic microscope (10×), and the sum total of theareas was taken as the ulcer index. To a control group was administered0.5% Tween 80 physiological saline.

The inhibition percentage was determined from the following equation:##EQU5##

The results are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                                Dose      Inhibition  ID.sub.50                                                                             Potency                                 Drug No.                                                                              (mg/kg)   percentage (%)                                                                            (mg/kg) ratio                                   ______________________________________                                        3       10        83**        1.72    9.0                                             3         73*                                                                 1         12                                                          9       10        86**        1.70    9.1                                             3         66*                                                                 1         33                                                          15      10        83**        1.35    11.5                                            3         69*                                                                 1         42                                                          29      3         78*         1.40    11.1                                            1         37                                                          33      3         75*         1.58    9.8                                             1         32                                                          Cimetidine                                                                            30        94**        15.5    1                                               10        22                                                          Ranitidine                                                                            10        80**        6.4     2.4                                             3         7           6.4     2.4                                     ______________________________________                                         Note:-                                                                        *p < 0.05                                                                     **p < 0.01                                                               

(iv) Reserpine ulcer

An experiment was carried out according to the method of Adami et al.[E. Adami et al., Arch. int. Pharmacodyn., 147, 113 (1964)].

Ten Wistar strain rats (male, 180 to 200 g) per group were starved for30 hours, after which each drug was orally administered, and after 1hour, reserpine was injected subcutaneously at a dose of 10 mg/kg. After18 hours, the stomach was removed and fixed with 3% formalin, andthereafter the lengths of the ulcers formed in the stomach were measuredwith callipers. The measured values were converted to the scoresdescribed below, and the sum total of the scores was taken as the ulcerindex.

That is to say, 1 to 5 pin point ulcers are scored as 1, 6 or more pinpoint ulcers are scored as 2, ulcers of 1 mm or less in length arescored as 1, ulcers of 1 to 2 mm in length are scored as 2, ulcers of 2to 4 mm in length are scored as 4, and ulcers of 4 mm or more in lengthare scored as 8.

To a control group was administered 0.5% Tween 80 physiological saline.The inhibition percentage was determined from the following equation:##EQU6##

The results are shown in Table 7.

                  TABLE 7                                                         ______________________________________                                                             Inhibition                                               Drug No. Dose (mg/kg)                                                                              percentage (%)                                                                            ID.sub.50 (mg/kg)                            ______________________________________                                         9       3           69**        1.8                                                   1           29                                                       29       3           41**        4.7                                                   1           21                                                       32       3           55**        2.15                                                  1           38                                                       33       3           68*         1.4                                                   1           42                                                       40       3           50**        3.0                                                   1           36*                                                      Cimetidine                                                                             100         9.7         --                                           Ranitidine                                                                             100         40          --                                                    30          33                                                       ______________________________________                                         Note:-                                                                        *p < 0.05                                                                     **p < 0.01?                                                              

[IV] Acute toxicity

Each of 45 drugs was orally administered to ICR strain mice (male, 20 to25 g), and the mice were observed until after 1 week.

The results are shown in Table 8.

                  TABLE 8                                                         ______________________________________                                                             Number of died animals/                                  Drug No.  Dose (mg/kg)                                                                             Number of animals used                                   ______________________________________                                        1-45      1000       0/5                                                      ______________________________________                                    

From Tables 1 to 8, it is evident that the amine derivatives of thegeneral formula (I) and the salts thereof have a potent inhibitoryactivity on gastric acid secretion and a long duration of the activity,have a potent anti-ulcer activity, have a low toxicity and thereforehave a wide safety margin.

The process for producing an amine derivative of the general formula (I)or a salt thereof is described below.

The amine derivative of the general formula (I) or the salt thereof areproduced by the production processes hereinafter described, per sewell-known processes and processes according thereto. ##STR10##

In the formula, Q¹ and Q⁵, which may be the same or different, areremovable groups; Q² is a group which forms an oxy or thio linkage or aremovable group; and in the case of p being 0, Q² is a group which formsan oxy or thio linkage; Q³ is a removable group in the case of Q² beinga group which forms an oxy or thio linkage, and is a group which formsan oxy or thio linkage in the case of Q² being a removable group, R^(1a)is a substituted or unsubstituted heterocyclic group; p¹ is 1, 2 or 3;R^(1b) is a substituted or unsubstituted heterocyclic group; Q⁴ is aremovable group; and R¹, R², R³, p, q, X, Y and Z have the same meaningsas defined above. As the heterocyclic groups for R^(1a) and R^(1b),there may be used the same heterocyclic groups as described above forR¹, and the substituents for them include the same substituents asdescribed for R¹.

Each of the production processes is described below in detail.

(I) Production Processes A and B

Production Processes A and B can be carried out in substantially thesame manner.

(a) These production processes can be carried out by reacting a compoundrepresented by the formula [IV] with a compound represented by theformula [V] or a salt thereof, or reacting a compound represented by theformula [VI] with a compound represented by the formula [II] or a saltthereof, in the presence or absence of a solvent.

The removable groups for Q¹ in the formulas [IV] and [VI] includeconventional removable groups, for example, halogen atoms; alkylthiogroups; alkylsulfinyl groups; aralkylthio group such as benzylthio andthe like; alkoxy groups; 1-imidazolyl group; 3,5-dimethylpyrazolylgroup; etc.

The salts of the compounds of the formulas [II] and [V] include thesalts exemplified in the case of the salts of the amine derivative ofthe general formula [I]. However, in the case of salts with acid, it ispreferable to treat the salts with a suitable base, for example, analkali metal alkoxide such as sodium methoxide or the like, an alkalihyroxide such as potassium hydroxide, sodium hydroxide or the like, oran alkali carbonate such as potassium carbonate, sodium carbonate or thelike and use them in the free state.

As the solvent, any solvent may be used without any particularlimitation so long as it has no adverse effect on the reaction, andthere may be used alcohols such as methanol, ethanol, isopropanol,ethylene glycol and the like; nitriles such as acetonitrile,propionitrile and the like; ethers such as diethyl ether, diisopropylether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane and the like;halogenated hydrocarbons such as methylene chloride, chloroform,1,2-dichloroethane and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; dimethylsulfoxide; pyridine; water;etc., alone or in admixture of two or more.

Further, in effecting the reaction, it is preferable in some cases touse a base or a heavy metal salt. The base includes inorganic bases, forexample, alkali hydroxides such as potassium hydroxide, sodium hydroxideand the like; alkali carbonates such as potassium carbonate, sodiumcarbonate and the like; and alkali hydrogencarbonates such as potassiumhydrogencarbonate, sodium hydrogencarbonate and the like, or organicbases, for example, tertiary amines such as triethylamine,N-methylmorpholine, N-methylpiperidine, pyridine and the like. It isalso possible to use an excess of the compound of the formula [II] or[V] to serve as the base. The heavy metal salt includes silver nitrate,lead tetraacetate, mercuric acetate and the like.

These starting compounds have geometrical isomers, tautomers, opticalisomers and racemic isomers, and all of them may be used in theaforesaid processes. In particular, since the compounds of the formulas[V] and [VI] have an asymmetric carbon atom in the molecule, it ispreferable to use optically active forms of the compounds of theformulas [V] and [VI] when producing an optically active form of anamine derivative of the formula [I] or a salt thereof.

The amounts of the compounds of the formulas [II] and [V] or saltsthereof used are preferable at least equimolar to those of the compoundsof the formulas [VI] and [IV].

Although the reaction temperature and the reaction time are not criticaland may properly be varied depending on the reactants and the like, thereaction is conducted preferably at -5° C. to 200° C., more preferably5° C. to 120° C, for 10 minutes to 48 hours.

(b) The compound of the formula [IV] or [VI] can be obtained by reactingthe compound of the formulas [II] or [V] or a salt thereof with acompound of the formula [III] in the presence or absence of a solvent.

Q¹ and Q⁵ in the formula [III], which may be the same or different, areremovable groups, and the removable group for Q⁵ includes the samegroups as described for Q¹ in the above-mentioned formulas [IV] and[VI].

The reaction may be effected under substantially the same conditions asin above (a). However, when R³ is a hydrogen atom in the reaction of acompound of the formula [V] or a salt thereof with a compound of theformula [III], it is preferable to effect the reaction at -30° C. to 40°C., though the reaction temperature may be varied depending on thereactants.

The amount of the compound of the formula [III] used is preferable atleast equimolar to the amount of the compound of the formula [II] or [V]or a salt thereof. And, it is possible to use the obtained compound ofthe formula [IV] or [VI], as the starting compound for the subsequentreaction without isolating the same.

(II) Production Process C

This production process is carried out by reacting a compoundrepresented by the formula [II] or a salt thereof with a compoundrepresented by the formula [VII] or a salt thereof in the presence orabsence of a solvent, and then, if desired, introducing ahydroxyl-protecting group by a conventional method.

The salt of the compound of the formula [VII] includes salt with alkalimetals such as potassium, sodium and the like; salts with alkaline earthmetals such as calcium, magnesium and the like; and salts with tertiaryamines such as triethylamine and the like.

As the solvent used in the reaction, any solvent may be used without anyparticular limitation so long as it has no adverse effect on thereaction. Specifically, there may be exemplified the same solvents asexemplified in the production processes A and B.

The amount of the compound of the formula [VII] or the salt thereof usedis preferable at least equimolar to that of the compound of the formula[II] or the salt thereof.

Although the reaction temperature and the reaction time are not criticaland may properly be varied depending on the reactants and the like, thereaction is effected at preferably -5° C. to 200° C., more preferably20° C. to 120° C., for 10 minutes to 48 hours.

The thus obtained compound is the compound of the formula [I] in whichR³ is a hydrogen atom, and therefore, the hydroxyl-protecting groupsdescribed above may, if desired, be introduced by a conventional methodto obtain a compound of the general formula [I] or a salt thereof inwhich R³ is a hydroxyl-protecting group.

(III) Production Process D

This production process is carried out by reacting a compoundrepresented by the formula [VIII] with a compound represented by theformula [IX] in the presence or absence of a solvent.

As the groups for Q² and Q³ in the formulas [VIII] and [IX] which canform an oxy linkage, there may be used, for example, hydroxyl group andthe like, and as those which can form a thio linkage, there may be used,for example, mercapto group, amidinothio group and the like. As theremovable groups for Q² and Q³, there may be used, for example, halogenatoms; acyloxy groups such as acetoxy and the like; substituted orunsubstituted arylsulfonyloxy groups, such as benzenesulfonyloxy,4-methylbenzenesufonyloxy and the like, etc.

As the solvent used in the reaction, any solvent may be used without anyparticular limitation so long as it has no adverse effect on thereaction. The solvents may be used alone or in admixture of two or more,and include, for example, alcohols such as methanol, ethanol,isopropanol, ethylene glycol and the like; ethers such astetrahydrofuran, dioxane and the like; ketones such as acetone and thelike; amides such as N,N-dimethylformamide, N,N-dimethylacetamide andthe like; water; etc.

The reaction is preferably effected under basic conditions, and thebases which may be used for this purpose include inorganic bases, forexample, alkali metal alkoxides such as potassium methoxide, sodiummethoxide and the like; alkali hydroxides such as potassium hydroxide,sodium hydroxide and the like; alkali carbonates such as potassiumcarbonate, sodium carbonate and the like; alkaline earth metalhydroxides such as calcium hydroxide and the like, or organic bases, forexample, tertiary amines such as triethylamine and the like; etc.

Further, this reaction is preferably effected in an inert gasatmosphere, for example, in a nitrogen gas atmosphere.

Although the reaction temperature and the reaction time are not criticaland may properly be varied depending on the reactants and the like, thereaction may preferably be conducted at -20° C. to 120° C. for 10minutes to 48 hours.

In addition, the reaction may also be effected in a two-phase systemconsisting of water and a solvent which is not miscible with water, forexample, chloroform or the like, in the presence of a phase transfercatalyst, for example, a quaternary ammonium salt such asbenzyltriethylammonium chloride or the like, and any of theabove-mentioned bases.

(IV) Production Process E

This production process is carried out by reacting a compound of theformula [X] with a compound of the formula [XI] in the presence orabsence of a solvent.

As the solvent used in this reaction, any solvent may be used withoutany particular limitation so long as it has no adverse effect on thereaction, and the solvent includes ethers such as tetrahydrofuran,dioxane and the like; nitriles such as acetonitrile, propionitrile andthe like; aromatic hydrocarbons such as benzene, toluene and the like;amides such as N,N-dimethylformamide, N,N-dimethylacetamide and thelike; water; alcohols such as methanol, ethanol and the like; etc. whichmay be used alone or in admixture of two or more.

In effecting the reaction, it is preferable in some cases to use a base,which includes, for example, the bases exemplified in Production ProcessD.

This reaction is preferably effected in an inert gas atmosphere, forexample, in a nitrogen gas atmosphere.

Although the reaction temperature and the reaction time are not criticaland may be properly varied depending on the reactants and the like, thereaction is effected at preferably -10° C. to 150° C., more preferablyroom temperature to 100° C., for 10 minutes to 24 hours.

And, the reaction is preferably effected for a compound [XI] in which R³is a hydroxyl-protecting group. The hydroxyl-protecting group of thethus obtained compound can be removed in a conventional manner to obtaina compound in which R³ is a hydrogen atom.

(V) Production Process F

This production process is carried out by reacting a compoundrepresented by the formula [XII] with a compound represented by theformula [XIII] in the presence of a catalyst in the presence or absenceof a solvent.

The removable group for Q⁴ in the formula [XII] includes, for example,alkoxy groups, aryloxy groups, acyloxy groups and the like.

As the solvent used in the reaction, any solvent may be used without anyparticular limitation so long as it has no adverse effect on thereaction, and the solvent includes, for example, carboxylic acids suchas acetic acid, butyric acid and the like; halogenated hydrocarbons suchas methylene chloride, chloroform, 1,2-dichloroethane and the like;esters such as ethyl acetate, butyl acetate and the like; ethers such astetrahydrofuran, dioxane and the like; etc.

The catalyst includes Lewis acids such as boron trifluoride and thelike; complex compounds of Lewis acids, such as boron trifluoride-aceticacid complex compound and protonic acids such as hydrogen chloride,sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid and thelike. In the present reaction, these compounds may also be used assolvents.

Although the reaction temperature and the reaction time are not criticaland may be properly varied depending on the reactants and the like, thereaction is preferably effected at 0° C. to 50° C., for 30 minutes to 5hours.

(VI) Production Process G

This production process is carried out by reacting a compoundrepresented by the formula [X] with a compound represented by theformula [VII] or a salt thereof and ethyleneimine in the presence orabsence of a solvent, and then, if desired, protecting the hydroxylgroup.

As the solvent, any solvent may be used without any particularlimitation so long as it has no adverse effect on the reaction, andthere may be used alcohols such as methanol, ethanol, isopropanol,ethylene glycol and the like; nitriles such as acetonitrile,propionitrile and the like; ethers such as tetrahydrofuran, dioxane andthe like; halogenated hydrocarbons such as methylene chloride,chloroform, 1,2-dichloroethane and the like; aromatic hydrocarbons suchas benzene, toluene, xylene and the like; amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like;dimethylsulfoxide; water; etc.; alone or in admixture of two or more.

And, in effecting the reaction, it is preferable in some cases to use abase. The base includes the same bases as described in the ProductionProcess D.

Further, this reaction is preferably effected in an inert gasatmosphere, for example, in a nitrogen gas atmosphere.

The addition order of a compound represented by the formula [X], acompound represented by the formula [VII] or a salt thereof andethyleneimine is not critical and may properly be determined.

Although the reaction temperature and the reaction time are not criticaland may properly be varied depending on the reactants and the like, thereaction is effected at preferably -10° C. to 200° C. for 10 minutes to48 hours.

The thus obtained compound is the compound of the formula [Id] in whichR³ is a hydrogen atom, and therefore, the hydroxyl-protecting groupdescribed above may, if desired, be introduced by a conventional methodto obtain a compound of the formula [Id] or a salt thereof in which R³is a hydroxyl-protecting group.

Processes for producing the starting compounds in each of theabove-mentioned production processes are described below.

The starting compounds represented by the formulas [II], [III], [V], [X]and [XIII], though include novel compounds, too, are easily produced ina manner known per se, the methods described in the Examples whichappear hereinafter, and methods according thereto.

The starting compounds represented by the formulas [VII], [VIII], [IX],[XI] and [XII] are produced in the following manner:

(1) Process for producing the compound of the formula [VII] (route 1)

This process is carried out by reacting a compound represented by theformula [Va] or a salt thereof with a compound represented by theformula [III] in the presence or absence of a solvent. ##STR11##

The solvent may be any solvent so long as it has no adverse effect onthe reaction, and there is no particular limitation. Specifically, itincludes those exemplified above in Production Processes A and B.

The amount of the compound of the formula [III] used is preferably atleast equimolar to that of the compound of the formula [Va] or a saltthereof.

Although the reaction temperature and the reaction time are not criticaland may be properly varied depending on the reactants and the like, thereaction is effected preferably at 10° C. to 200° C. for 10 minutes to24 hours.

(2) Process for producing the compound of the formula [VIII] (route 2)

This process is carried out by a conventional method, and a compound[VIII] in which Q² is a halogen atom or an acyloxy group can easily beobtained, respectively, by halogenation or acylation of a compound[XIV], e.g., with thionyl chloride or with acetic anhydride. Further, acompound [VIII] in which Q² is an amidinothio group can easily beobtained, for example, by reacting a compound [XIV] with thiourea underacidic conditions. And the thus obtained compound [VIII] havingamidinothio group for Q² is hydrolyzed to obtain a compound [VIII]having mercapto group for Q².

(3) Process for producing the compound of the formula [IX] (route 3)

This process is carried out by reacting a compound represented by theformula [VI] with a compound represented by the formula [XV] or a saltthereof, or by reacting a compound represented by the formula [V] or asalt thereof with a compound represented by the formula [XVII] producedby reacting a compound represented by the formula [XV] or a salt thereofwith a compound represented by the formula [III].

The reaction can be effected in substantially the same manner as inProduction Processes A and B. Although the reaction temperature and thereaction time are not critical and may be properly varied depending onthe reactants and the like, the reaction is effected at preferably -30°C. to 200° C., more preferably -20° C. to 120° C., for 10 minutes to 48hours.

In some case, the reaction is preferably effected in a inert gasatmosphere, for example, in a nitrogen atmosphere.

(4) Process for producing the compound of the formula [XI] (route 3)

This process is carried out by reacting a compound represented by theformula [VI] with ethyleneimine represented by the formula [XVI] or asalt thereof, or by reacting a compound represented by the formula [XX]with a compound represented by the formula [V] or a salt thereof.

The reaction can be effected in substantially the same manner as inProduction Processes A and B.

Further, in this reaction, R³ is preferably a hydroxyl-protecting group,and in this case, the compound obtained may be used as it is as thestarting material in Production Process E.

(5) Process for producing the compound of the formula [XII] (route 4)

This process is carried out by reacting a compound represented by theformula [V] or a salt thereof with a compound of the formula [XIX] whichhas been produced by the reaction of a compound represented by theformula [XVIII] or a salt thereof with a compound represented by theformula [III], or by reacting a compound represented by the formula [VI]with a compound represented by the formula [XVIII] or a salt thereof.

This reaction can be effected in substantially the same manner as inProduction Processes A and B.

Some of these intermediates are novel compounds, which are included inthis invention.

The novel compounds are, for example, those represented by the followingformulas: ##STR12## wherein U is any of the removable groups describedfor Q¹ or an ethyleneimino group, and R², R³, Y and Z have the samemeanings as defined above, and ##STR13## wherein Z¹ is nitromethylenegroup an alkylsulfonylimino group, a substituted or unsubstitutedarylsulfonylimino group, a cyanoimino group, a sulfamoylimino group, andR² and Y have the same meanings as defined above, or a salt thereof.

In the above-mentioned production processes and the processes forproducing the starting compounds, active groups such as hydroxyl group,amino group, carboxyl group or the like can properly be protected with acorresponding protecting group and then subjected to removal thereof ina conventional manner.

The protecting groups for the hydroxyl group include those commonlyknown as protecting groups for hydroxy group, for example, thoseexemplified above as the hydroxyl-protecting group for R³. Theprotecting groups for the amino group include those commonly known asprotecting groups for amino group, for example, formyl group; C₂₋₅alkanoyl groups such as acetyl, propionyl, isovaleryl, pivalyol and thelike; aroyl groups such as benzoyl, toluoyl, 2-naphthoyl and the like;alkoxycarbonyl groups such as ethoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl and the like; halogeno-C₂₋₅ alkanoyl groups such asmonochloroacetyl, dichloroacetyl and the like; furoyl group; tritylgroup; 2-nitrophenylthio; 2,4-dinitrophenylthio; organicsilyl-containing groups such as trimethylsilyl, tert-butyldimethylsilyland the like; etc. The protecting groups for the carboxyl group includethose commonly known as protecting groups for carboxyl group, forexample, alkyl groups; benzyl group; p-nitrobenzyl group;p-methoxybenzyl group; diphenylmethyl group; trityl group; organicsilyl-containing groups such as trimethylsilyl, tert.-butyldimethylsilyland the like; etc.

The thus obtained amine derivative of the formula [I] or a salt thereofcan easily be isolated and collected by a conventional procedure, e.g.,recrystallization, concentration, extraction, optical resolution, columnchromatography or the like. A compound represented by the formula [I] inwhich R³ is a hydrogen atom can be further converted to a compoundrepresented by the formula [I] in which R³ is a hydroxyl-protectinggroup by a conventional method, and the compound in which R³ is ahydroxyl-protecting group can be converted to the compound in which R³is a hydrogen atom by removing the hydroxyl-protecting group by aconventional method. For example, a compound represented by the formula[I] in which R³ is a hydrogen atom can be converted to a compoundrepresented by the formula [I] in which R³ is an acyl group, e.g., anacetyl group, by subjecting the former to acylation. When R³ is ahydroxyl-protecting group, e.g., tert.-butyldimethylsilyl group, thisgroup can be removed by hydrolysis by the action of[tetra(n-butyl)]ammonium fluoride. A compound represented by the formula[I] in which R¹ or R² has a substituent, for example, a hydroxyl groupis converted by acylation to a desired compound in which R¹ or R² issubstituted by an acyloxy group. A compound represented by the formula[I] in which R¹ or R² has a nitro group as the substituent is convertedby reduction to a desired compound in which R¹ or R² has an amino groupas the substituent.

The amine derivative represented by the formula [I] or a salt thereofcan be thus converted to another desired compound in a conventionalmanner. Further, the salt of the amine derivative of the formula [I] caneasily be obtained from the amine derivative in the free state in aconventional manner.

Anti-ulcer agents containing the amine derivative of the general formula[I] or a salt thereof are prepared in a conventional manner in the formof tablets, hard capsules, soft capsules, granules, powder, finegranules, pills, troches, ointments, suppositories, injections,suspensions, emulsions, drops, syrups or the like, and can beadministered either orally or parenterally and in particular, oraladministration is preferred.

In order to prepare them in various forms suitable for oral orparenteral administration, the preparation may be carried out by usingpharmaceutically acceptable additives which are usually used, such asexcipients, binders, lubricants, disintegrators, bases for suppositoriesand the like. Further, if necessary, other additives may also be usedsuch as isotonicities, stabilizers, dispersants, antioxidants,colorants, perfumes, buffers and the like.

Other therapeutically useful medicines may also be incorporated.

The amine derivative of the formula [I] or the salt thereof is usuallyadministered orally or parenterally to an adult in a dosage of 0.001mg/kg to 10 mg/kg a day in 1 to 4 portions, though the dosage and theadministration time may properly be varied depending on theadministration route and the symptoms of patients.

Next, this invention is explained below referring to Examples andPreparation Examples, which are not by way of limitation but by way ofillustration.

EXAMPLE 1

(1) With 600 ml of ethanol were mixed 153 g of furfuryl alcohol, 128 gof dimethylamine hydrochloride and 70 g of paraformaldehyde, and theresulting mixture was subjected to reaction under reflux for 2 hours.Thereafter, 70 g of paraformaldehyde was further added, and the mixturethus obtained was subjected to reaction under reflux for 18 hours. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, and 500 ml of water and 86 g of anhydrous sodiumcarbonate were added to the resulting residue. The oily substanceseparated was extracted with three 500-ml portions of diethyl ether, andthe extracts were combined and then dried over anhydrous magnesiumsulfate, after which the solvent was removed by distillation underreduced pressure. The oily substance thus obtained was distilled underreduced pressure to obtain 105 g (yield 43.4%) of5-(dimethylamino)methyl-2-furfuryl alcohol having a boiling point of128°-133° C./15 mmHg.

(2) To a solution of 50.0 g cysteamine hydrochloride in 180 ml ofconcentrated hydrochloric acid was added dropwise 68.3 g of the5-(dimethylamino)methyl-2-furfuryl alcohol obtained in above (1) withstirring at 0° C. to 5° C. After the addition, resulting mixture wassubjected to reaction at 0° C. to 5° C. for 20 hours. Thereto was added400 ml of water, and the mixture thus obtained was neutralized withsodium carbonate, and then adjusted to a pH of 10 with 10N aqueoussodium hydroxide solution. The oily substance separated was extractedwith 500 ml of chloroform, and the extract was dried over anhydrousmagnesium sulfate, after which the solvent was removed by distillationunder reduced pressure to obtain 42.5 g (yield 45%) of2-{[5-(dimethylamino)methyl-2-furyl]methylthio}ethylamine having aboiling point of 120°-130° C./1 mmHg.

(3) The 200 ml of dioxane were added 40.0 g of the2-{[5-(dimethylamino)methyl-2-furyl]-methylthio}ethylamine obtained inabove (2) and 61.7 g of 1,1-bis(methylthio)-2-nitroethene, and theresulting mixture was subjected to reaction under reflux for 10 minutes.After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and 200 ml of ethanol was added tothe resulting residue, after which the insolubles were removed byfiltration. The solvent was removed by distillation under reducedpressure, and the resulting residue was purified by a columnchromatography (Wako Silica Gel C-200, eluent; chloroform:ethanol=30:1by volume) to obtain 44 g (yield 71.3%) of1-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethylamino}-1-methylthio-2-nitroethenehaving a melting point of 71° C.

(4) In 6 ml of ethanol were dissolved 1.0 g of the1-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethylamino}-1-methylthio-2-nitroetheneobtained in above

(3) and 2.0 g of DL-β-hydroxyphenethylamine, and the resulting solutionwas subjected to reaction under reflux for 2 hours. After completion ofthe reaction, the solvent was removed by distillation under reducedpressure, and the resulting residue was purified by a columnchromatography (Wako Silica Gel C-200, eluent; chloroform:ethanol=10:1by volume), and recrystallized from acetonitrile to obtain 0.95 g (yield71%) ofN-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediaminehaving a melting point of 115°-116° C.

Elementary analysis values (for C₂₀ H₂₈ N₄ O₄ S₁): Calculated (%): C:57.12, H: 6.71, N: 13.32; Found (%): C: 57.34, H: 6.97, N: 13.23.

The compounds listed in Table 9 were obtained in the same manner asdescribed above.

                  TABLE 9                                                         ______________________________________                                         ##STR14##                                                                    R.sup.2         Physical properties                                           ______________________________________                                         ##STR15##      Melting point: 131° C. Elementary analysis values                      (for C.sub.20 H.sub.28 N.sub.4 O.sub.5 S.sub.1) Calculated                     (%): C: 55.03, H: 6.46, N: 12.84 Found (%):C: 55.27, H:                      6.71, N: 13.00                                                 ##STR16##                                                                                     ##STR17##                                                                     ##STR18##                                                     ##STR19##                                                                                     ##STR20##                                                                     ##STR21##                                                     ##STR22##      Melting point: 130-131° C.                              ##STR23##                                                                                     ##STR24##                                                                     ##STR25##                                                     ##STR26##      Melting point: 132.5-133.5° C.                          ##STR27##      Melting point: 125-126° C.                              ##STR28##                                                                                     ##STR29##                                                                     ##STR30##                                                     ##STR31##      Melting point: 123-124° C.                              ##STR32##                                                                                     ##STR33##                                                                     ##STR34##                                                     ##STR35##      Melting point: 111-113° C.                              ##STR36##                                                                                     ##STR37##                                                                     ##STR38##                                                     ##STR39##                                                                                     ##STR40##                                                                     ##STR41##                                                     ##STR42##                                                                                     ##STR43##                                                                     ##STR44##                                                     ##STR45##      Melting point: 114° C.                                  ##STR46##      Melting point: 94-96° C.                                ##STR47##                                                                                     ##STR48##                                                                     ##STR49##                                                     ##STR50##                                                                                     ##STR51##                                                                    H), 6.14 (1H, d, furan ring H), 6.49                                          (1H, s, CH), 6.76-7.03 (2H, m,                                                thiophene ring H × 2), 7.23-7.42                                        (1H, m, thiophene ring H)                                      ##STR52##                                                                                     ##STR53##                                                                     ##STR54##                                                     ##STR55##                                                                                     ##STR56##                                                                     ##STR57##                                                     ##STR58##                                                                                     ##STR59##                                                                     ##STR60##                                                     ##STR61##                                                                                     ##STR62##                                                                     ##STR63##                                                     ##STR64##                                                                                     ##STR65##                                                                    H × 2), 6.76 (1H, s, CH),                                               7.28-7.52 (1H, m, pyridine ring H),                                           7.64-8.17 (2H, m, pyridine ring                                               H × 2), 8.75 (1H, m, pyridine                                           ring H)                                                        ##STR66##                                                                                     ##STR67##                                                                     ##STR68##                                                     ##STR69##                                                                                     ##STR70##                                                                     ##STR71##                                                     ##STR72##                                                                                     ##STR73##                                                                    6.25 (2H, s, furan ring H × 2),                                         6.68 (1H, s, CH), 7.48 (4H, s,                                                benzene ring H × 4)                                      ##STR74##                                                                                     ##STR75##                                                                     ##STR76##                                                     ##STR77##                                                                                     ##STR78##                                                                     ##STR79##                                                     ##STR80##                                                                                     ##STR81##                                                                     ##STR82##                                                     ##STR83##      Melting point: 110-112° C.                              ##STR84##      Melting point: 130-132° C.                              ##STR85##                                                                                     ##STR86##                                                                     ##STR87##                                                     ##STR88##      Melting point: 138-139° C.                             ______________________________________                                    

EXAMPLE 2

(1) In 200 ml of methylene chloride were dissolved 20.8 g of3-methyl-2-thenyl alcohol and 27.1 ml of triethylamine, and 12.9 ml ofthionyl chloride was added thereto dropwise at -15° C. to -10° C. over aperiod of 30 minutes, after which the resulting solution was furthersubjected to reaction at the same temperature for 30 minutes. Thereaction mixture was poured into ice water, and the organic layer wasseparated and then dried over anhydrous magnesium sulfate. Subsequently,the dried organic layer was added dropwise with ice-cooling to asolution of 95 g of dimethylamine in 550 ml of ethanol, and theresulting mixture was allowed to stand overnight at room temperature.The solvent was removed by distillation under reduced pressure, afterwhich 100 ml of water was added to the residue, and the resultingmixture was adjusted to pH 10 with potassium carbonate, and thenextracted with 200 ml of ethyl acetate. The extract was washed with 50ml of a saturated aqueous sodium chloride solution and dried overanhydrous potassium carbonate, after which the solvent was removed bydistillation under reduced pressure, and the oily substance thusobtained was distilled under reduced pressure to obtain 19.0 g (yield75%) of 2-(dimethylamino)methyl-3-methylthiophene having a boiling pointof 85°-86° C./14 mmHg.

(2) In 70 ml of anhydrous tetrahydrofuran was dissolved 15.5 g of the2-(dimethylamino)methyl-3-methylthiophene obtained in above (1), and 70ml of a n-butyllithium-n-hexane solution (15% by weight solution) wasadded dropwise at -20° C. to -10° C. in a nitrogen atmosphere. After theaddition, the temperature of the resulting solution was graduallyraised, and the solution was subjected to reaction at room temperaturefor 4 hours. After completion of the reaction, 3.6 g of paraformaldehydewas added to the solution with ice-cooling, and the resulting mixturewas further subjected to reaction for 2 hours after the generation ofheat ceased. After completion of the reaction, the solvent was removedby distillation under reduced pressure, and 20 ml of ice water and 100ml of chloroform were added to the resulting residue, after which theorganic layer was separated. The organic layer was washed successivelywith 20 ml of water and 10 ml of a saturated aqueous sodium chloridesolution, and then dried over anhydrous magnesium sulfate, after whichthe solvent was removed by distillation under reduced pressure, and theunreacted materials were removed from the oily substance thus obtainedby distillation under reduced pressure on an oil bath at 110° C. to 115°C. to obtain 17.0 g (yield 92%) of crude5-(dimethylamino)-methyl-4-methyl-2-thenyl alcohol.

(3) To a solution of 15.6 g of cysteamine hydrochloride in 115 ml ofconcentrated hydrochloric acid was added 17.0 g of the crude5-(dimethylamino)methyl-4-methyl-2-thenyl alcohol obtained in above (2)at 0° C., and the resulting mixture was subjected to reaction at roomtemperature for 2 days. After completion of the reaction, sodiumcarbonate was gradually added with ice-cooling until the waterdisappeared, and the separated oily substance was extracted with 200 mlof ethyl acetate. The extract was dried over anhydrous potassiumcarbonate, and the solvent was removed by distillation under reducedpressure to obtain 20.4 g (yield 91%) of yellow, oily, crude2-{[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio}ethylamine.

(4) With 70 ml of acetonitrile were mixed 14.0 g of the crude2-{[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio}ethylamineobtained in above (3) and 19.0 g of 1,1-bis(methylthio)-2-nitroethene,and the resulting mixture was subjected to reaction under reflux for 2hours. After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and 30 ml of ethanol was added tothe resulting residue, after which the insolubles were removed byfiltration. The solvent was removed by distillation under reducedpressure, and the resulting residue was purified by a columnchromatography (Wako Silica Gel C-200, eluent; chloroform:methanol=30:1by volume) to obtain 19.0 g (yield 92%) of1-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethylamino}-1-methylthio-2-nitroethanehaving a melting point of 69°-71° C.

NMR (CDCl₃) δ values: 2.13 (3H, s, --CH₃), 2.27 (6H, s, --CH₃ ×2), 2.46(3H, s, --CH₃), 2.79 (2H, t, >CH₂), 3.45-3.85 (2H, m, >CH₂), 3.51 (2H,s, >CH₂), 3.91 (2H, s, >CH₂), 6.60 (1H, s, ═CH--), 6.71 (1H, s,thiophene ring H), 10.6 (1H, bs, >NH).

(5) With 6 ml of ethanol were mixed 0.60 g of the1-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethylamino}-1-methylthio-2-nitroetheneobtained in above (4) and 1.10 g ofDL-[2-(4-ethylphenyl)-2-hydroxyethyl]amine, and the resulting mixturewas subjected to reaction under reflux for 1 hour. After completion ofthe reaction, the solvent was removed by distillation under reducedpressure, and the resulting residue was purified by a columnchromatography (Wako Silica Gel C-200, eluent; chloroform:ethanol=20:1by volume) and crystallized from isopropanol-diethyl ether solution toobtain 0.55 g (yield 69%) ofN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(4-ethylphenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediaminehaving a melting point of 112°-115° C.

Elementary analysis values (for C₂₃ H₃₄ N₄ O₃ S₂): Calculated (%): C:57.71, H: 7.16, N: 11.70; Found (%): C: 57.82, H: 7.19, N: 11.43.

The compounds shown in Table 10 were obtained in the same manner asdescribed above.

                  TABLE 10                                                        ______________________________________                                         ##STR89##                                                                    R.sup.2         Physical properties                                           ______________________________________                                         ##STR90##                                                                                     ##STR91##                                                                     ##STR92##                                                                     ##STR93##                                                                     ##STR94##                                                                    (1H, s, CH), 6.72 (1H, s,                                                     thiophene ring H), 7.42 (5H, s,                                               benzene ring H × 5), 10.3 (1H,                                           ##STR95##                                                     ##STR96##                                                                                     ##STR97##                                                                     ##STR98##                                                                     ##STR99##                                                                    (1H, bs, OH), 6.62 (1H, s,                                                    CH), 6.81 (1H, s,                                                             thiophene ring H), 6.83,                                                      7.33 (4H, AA', BB', benzene ring                                              H × 4)                                                   ##STR100##                                                                                    ##STR101##                                                                    ##STR102##                                                                   5.7 (1H, bs, OH), 6.4-7.35 (6H, m,                                            benzene ring H × 4, thiophene ring                                       ##STR103##                                                    ##STR104##                                                                                    ##STR105##                                                                    ##STR106##                                                                   3.81 (3H, s, CH.sub.3), 4.95 (1H, m,                                           ##STR107##                                                                   6.76 (1H, s, thiophene ring H),                                               6.97, 7.41 (4H, AA', BB', benzene                                             ring H × 4)                                              ##STR108##                                                                                    ##STR109##                                                                   3.85 (3H, s, CH.sub.3), 3.93 (2H, s,                                           ##STR110##                                                                   (1H, s, CH), 6.7-7.6 (5H, m,                                                  thiophene ring H, benzene ring                                                 ##STR111##                                                    ##STR112##                                                                                    ##STR113##                                                                    ##STR114##                                                                    ##STR115##                                                                    ##STR116##                                                                   CH, benzene ring H × 4, thio-                                            ##STR117##                                                    ##STR118##                                                                                    ##STR119##                                                                    ##STR120##                                                                    ##STR121##                                                                    ##STR122##                                                                   (1H, s, CH), 6.66 (1H, s,                                                     thiophene ring H), 6.75-7.6 (4H,                                              m, benzene ring H × 4), 10.2 (1H,                                        ##STR123##                                                    ##STR124##                                                                                    ##STR125##                                                                    ##STR126##                                                                   (1H, s, CH), 6.68 (1H, s, thio-                                               phene ring H), 6.75-7.5 (4H, m,                                               benzene ring H × 4)                                      ##STR127##                                                                                    ##STR128##                                                                    ##STR129##                                                                   (1H, s, CH), 6.68 (1H, s, thio-                                               phene ring H), 6.75-7.8 (4H, m,                                               benzene ring H × 4)                                      ##STR130##                                                                                    ##STR131##                                                                    ##STR132##                                                                    ##STR133##                                                                   (1H, s, CH), 6.65 (1H, s, - thiophene ring H), 7.32 (4H,                      s,                                                                            benzene ring H × 4)                                      ##STR134##                                                                                    ##STR135##                                                                    ##STR136##                                                                    ##STR137##                                                                   (1H, s, thiophene ring H), 7.0-7.6                                            (4H, m, benzene ring H × 4), 10.2                                        ##STR138##                                                    ##STR139##                                                                                    ##STR140##                                                                    ##STR141##                                                                    ##STR142##                                                                   (1H, s, thiophene ring H), 7.1-7.95                                           (4H, m, benzene ring H × 4),                                             ##STR143##                                                    ##STR144##                                                                                    ##STR145##                                                                    ##STR146##                                                                    ##STR147##                                                                   CH), 6.73 (1H, s, thiophene                                                   ring H), 6.95-7.55 (4H, m, benzene                                             ##STR148##                                                    ##STR149##                                                                                    ##STR150##                                                                    ##STR151##                                                                    ##STR152##                                                                   6.66 (1H, s, CH), 6.78 (1H, s,                                                thiophene ring H), 7.05-7.8 (4H,                                              m, benzene ring H × 4)                                   ##STR153##                                                                                    ##STR154##                                                                    ##STR155##                                                                   (2H, s, OCH.sub.2 O), 6.68 (1H, s,                                            CH), 6.78 (1H, s, thiophene                                                   ring H), 6.85-7.1 (3H, m, benzene                                              ##STR156##                                                                    ##STR157##                                                    ##STR158##     Melting point: 137-139° C. (recrystallized from                        ethanol)                                                       ##STR159##     Melting point: 133-135° C. (recrystallized from                        ethanoldiethyl ether)                                          ##STR160##     Melting point: 92-95° C. (recrystallized from                          isopropanol- diethyl ether)                                    ##STR161##                                                                                    ##STR162##                                                                    ##STR163##                                                                    ##STR164##                                                                   thiophene ring H × 4), 10.3 (1H,                                         ##STR165##                                                    ##STR166##                                                                                    ##STR167##                                                                    ##STR168##                                                                   (2H, bs, furan ring H × 2), 6.51                                        (1H, s, CH), 6.60 (1H, s, thio-                                               phene ring H), 7.15-7.45 (1H, m,                                              furan ring H)                                                  ##STR169##                                                                                    ##STR170##                                                                    ##STR171##                                                                    ##STR172##                                                                    ##STR173##                                                                   OH), 6.3-7.05 (4H, m,                                                         CH, thiophene                                                                  ##STR174##                                                    ##STR175##                                                                                    ##STR176##                                                                    ##STR177##                                                                   (1H, bs, OH), 6.66 (1H, s,                                                    CH), 6.75 (1H, s,                                                             thiophene ring H),                                                            7.2-7.55, 7.7-8.1 (2H, m, pyridine                                            ring H × 2), 8.45-8.8 (2H,m,                                            pyridine ring H × 2), 10.4 (1H,                                          ##STR178##                                                    ##STR179##     Melting point: 108-111° C. (Recrystallized from                        isopropanol)                                                   ##STR180##                                                                                    ##STR181##                                                                    ##STR182##                                                                    ##STR183##                                                                   6.67 (1H, s, CH), 6.77 (1H, s,                                                thiophene ring H), 7.02-7.49 (4H,                                             m, benzene ring H × 4), 10.28                                            ##STR184##                                                    ##STR185##                                                                                    ##STR186##                                                                    ##STR187##                                                                    ##STR188##                                                                   (1H, s, thiophene ring H), 7.10-                                              7.41 (4H, m, benzene ring H × 4),                                        ##STR189##                                                    ##STR190##     Melting point: 109-112° C.                              ##STR191##     Melting point: 116-118° C.                              ##STR192##                                                                                    ##STR193##                                                                    ##STR194##                                                                    ##STR195##                                                                   5.55 (1H, bs, OH), 6.59 (1H, s,                                               CH), 6.69 (1H, s, thiophene                                                   ring H), 6.72, 7.27 (4H, AA', BB',                                            benzene ring H × 4), 10.25 (1H,                                          ##STR196##                                                    ##STR197##                                                                                    ##STR198##                                                                    ##STR199##                                                                    ##STR200##                                                                    ##STR201##                                                                   (1H, bs, OH), 6.60 (1H, s, CH),                                               6.67 (1H, s,thiophene ring H)                                                 7.0-7.50 (4H, m, benzene ring H                                               × 4)                                                     ##STR202##     Melting point: 108-110° C.                              ##STR203##                                                                                    ##STR204##                                                                    ##STR205##                                                                    ##STR206##                                                                    ##STR207##                                                                   CH), 6.73 (1H, s, thiophene                                                   ring H), 7.66 (4H, s, benzene                                                 ring H × 4)                                              ##STR208##                                                                                    ##STR209##                                                                    ##STR210##                                                                    ##STR211##                                                                   (1H, s, CH), 6.62 (1H, s,                                                     thiophene ring H), 6.40-7.40                                                  (3H, m, benzene ring H × 3), 7.60                                        ##STR212##                                                                    ##STR213##                                                    ##STR214##                                                                                    ##STR215##                                                                   (5H, m, benzene ring H × 3,                                             thiophene ring H, CH), 10.32                                                   ##STR216##                                                    ##STR217##                                                                                    ##STR218##                                                                    ##STR219##                                                                   6.55-6.85 (4H, m, benzene ring                                                H ×  3, thiophene ring H), 10.33                                         ##STR220##                                                    ##STR221##                                                                                    ##STR222##                                                                    ##STR223##                                                                   (4H, m, CH, benzene ring                                                      H × 2, thiophene ring H),                                                ##STR224##                                                    ##STR225##                                                                                    ##STR226##                                                                    ##STR227##                                                                    ##STR228##                                                                   CH), 6.74 (1H, s, thiophene                                                   ring H), 6.89-7.44 (4H, m, benzene                                             ##STR229##                                                    ##STR230##     Melting point: 119-122° C.                              ##STR231##                                                                                    ##STR232##                                                                    ##STR233##                                                                    ##STR234##                                                                   6.79 (1H, s, thiophene ring H),                                               7.25-7.85 (4H, m, benzene ring H                                              × 4)                                                    ______________________________________                                    

EXAMPLE 3

(1) In a mixture of 60 ml of ethanol and 200 ml of xylene was dissolved40 g of DL-β-hydroxyphenethylamine, and the resulting solution was addeddropwise to a solution of 57.8 g of 1,1-bis(methylthio)-2-nitroethene in600 ml of xylene under reflux over a period of 1.5 hours to effectreaction. During the reaction, the low-boiling fractions were graduallyremoved by distillation and the reaction temperature was maintained at130° C. to 140° C. After completion of the reaction, crystals weredeposited with stirring under ice-cooling. The crystals deposited werecollected by filtration, dried, and then mixed with 200 ml of a 5% (byweight) aqueous sodium hydroxide solution. After a slight amount ofinsolubles were removed by filtration, the filtrate was adjusted to pH 6with a 10% (by weight) aqueous acetic acid solution, and the crystalsdeposited were collected by filtration and dried to obtain 34 g of2-nitromethylene-5-phenyloxazolidine having a melting point of 139°-141°C.

On the other hand, the filtrate after the reaction was concentrated, and50 ml of ethanol was added to the resulting residue, after which thecrystals formed were collected by filtration. The crystals obtained weremixed with 25 ml of a 5% (by weight) aqueous sodium hydroxide solution,and the insolubles were removed by filtration. The filtrate was adjustedto pH 6 with 10% by weight aqueous acetic acid solution, and thecrystals deposited were collected by filtration and dried to obtain 4.8g (total yield: 64.5%) of 2-nitromethylene-5-phenyloxazolidine.

NMR (d₆ -DMSO) δ values: 3.65-4.52 (2H, m, >CH₂), 6.05 (1H, t, .tbd.CH),6.80 (1H, s, ═CH--), 7.54 (5H, s, benzene ring H×5), 10.1 (1H, bs, >NH).

The following compounds were obtained in the same manner as describedabove:

5-(3-Methylphenyl)-2-nitromethyleneoxazolidine

Melting point: 96°-97° C.

NMR (CDCl₃) δ values: 2.37 (3H, s, --CH₃), 3.69-4.50 (2H, m, >CH₂), 5.79(1H, t, .tbd.CH), 6.72 (1H, s, ═CH--), 6.80-7.55 (4H, m, benzene ringH×4), 9.2 (1H, bs, >NH).

5-(3-Methoxyphenyl)-2-nitromethyleneoxazolidine

Melting point: 105°-107° C.

NMR (d₆ -DMSO) δ values: 3.64-4.55 (2H, m, >CH₂), 3.87 (3H, s, --OCH₃),6.02 (1H, t, .tbd.CH), 6.79 (1H, s, ═CH--), 6.9-7.65 (4H, m, benzenering H×4).

5-(4-Fluorophenyl)-2-nitromethyleneoxazolidine

Melting point: 116°-118.5° C.

NMR (d₆ -DMSO) δ values: 3.48-4.56 (2H, m, >CH₂), 6.10 (1H, dd,.tbd.CH), 6.80 (1H, s, ═CH--), 7.20-7.85 (4H, m, benzene ring H×4),10.06 (1H, bs, >NH).

2-[(Dimethylamino)sulfonyl]imino-5-phenyloxazolidine

Melting point: 95°-98° C.

NMR (d₆ -DMSO) δ values: 2.71 (6H, s, --CH₃ ×2), 3.48-4.34 (2H, m,>CH₂), 5.95 (1H, t, .tbd.CH), 7.52 (5H, s, benzene ring H×5), 8.67 (1H,s, >NH).

2-(Methanesulfonyl)imino-5-phenyloxazolidine

Melting point: 120°-122° C.

NMR (d₆ -DMSO) δ values: 2.95 (3H, s, --CH₃), 3.43-4.31 (2H, m, >CH₂),5.98 (1H, t, .tbd.CH), 7.53 (5H, s, benzene ring H×5), 8.85 (1H, s,>NH).

2-Cyanoimino-5-phenyloxazolidine

Melting point: 117°-119° C.

NMR (d₆ -DMSO) δ values: 3.59-4.38 (2H, m, >CH₂), 6.08 (1H, t, .tbd.CH),7.58 (5H, s, benzene ring H×5), 9.50 (1H, bs, >NH).

5-(3-Bromophenyl)-2-nitromethyleneoxazolidine

Melting point: 120°-121° C.

NMR (CDCl₃) δ values: 3.76-4.60 (2H, m, >CH₂), 5.93 (1H, t, .tbd.CH),6.85 (1H, s, ═CH--), 7.39-7.69 (4H, m, benzene ring H×4), 9.30 (1H, bs,>NH).

(2) In 3 ml of ethanol were dissolved 1.5 g of2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethylamine and1.6 g of 5-(3-methylphenyl)-2-nitromethyleneoxazolidine obtained inabove (1), and the resulting solution was subjected to reaction at roomtemperature for 18 hours. After completion of the reaction, the solventwas removed by distillation under reduced pressure, and the resultingresidue was dissolved in 50 ml of ethyl acetate. The resulting solutionwas washed successively with 30 ml of 1N aqueous sodium hydroxidesolution and 30 ml of a saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate, after which the solvent wasremoved by distillation under reduced pressure. The resulting residuewas purified by a column chromatography (Wako Silica Gel C-200, eluent;chloroform:ethanol=20:1 by volume) to obtain 2.0 g (yield 70%) ofN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methylphenyl)ethyl]-2-nitro-1,1-ethenediamine having a melting point of 88°-89° C.

The physical property (NMR) of this product was identical with that inExample 2.

The following compounds were obtained in the same manner as describedabove.

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-(.beta.-hydroxyphenethyl)-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

The physical properties of these compounds were identical with those inExample 2.

EXAMPLE 4

(1) In 35 ml of 21% (by weight) hydrochloric acid-isopropanol solutionwas suspended 2.1 g of thiourea, and 5 g of5-(dimethylamino)methyl-4-methyl-2-thenyl alcohol was added thereto,after which the resulting mixture was subjected to reaction under refluxfor 15 hours. After the mixture was allowed to stand at roomtemperature, the crystals deposited were collected by filtration toobtain 7 g (yield 82%) of2-amidinothiomethyl-5-(dimethylamino)methyl-4-methylthiophenedihydrochloride having a melting point of 212°-214° C. (decomp.).

NMR (d₆ -DMSO) δ values: 2.31 (3H, s, --CH₃), 2.82 (6H, s, --CH₃ ×2),4.58 (2H, s, >CH₂), 5.04 (2H, s, >CH₂), 7.16 (1H, s, thiophene ring H),9.76 (4H, bs, ##STR235## 11.01 (1H, bs, HCl).

(2) In 5 ml of water was dissolved 10 g of2-amidinothiomethyl-5-(dimethylamino)methyl-4-methylthiophenedihydrochloride, and 2.52 g of sodium hydroxide was added thereto, andthe resulting mixture was subjected to reaction under reflux for 2.5hours in a nitrogen atmosphere. The reaction mixture was cooled to roomtemperature, and then extracted with 100 ml of methylene chloride, andthe extract was dried over anhydrous magnesium sulfate, after which thesolvent was removed by distillation under reduced pressure. The oilysubstance thus obtained was distilled under reduced pressure in anitrogen atmosphere to obtain 5.3 g (yield 83%) of5-(dimethylamino)methyl-2-mercaptomethyl-4-methylthiophene having aboiling point of 102°-105° C./3 mmHg.

NMR (CDCl₃) δ values: 2.14 (3H, s, --CH₃), 2.28 (6H, s, --CH₃ ×2), 3.48(2H, s, >CH₂), 3.85 (2H, s, >CH₂), 6.65 (1H, s, thiophene ring H).

(3) In 1 ml of chloroform were dissolved 0.29 g of1-aziridino-1-methylthio-2-nitroethene and 0.33 g of5-(dimethylamino)methyl-2-mercaptomethyl-4-methylthiophene obtained inabove (2), and the resulting solution was subjected to reaction at roomtemperature for 4 hours in a nitrogen atmosphere. After completion ofthe reaction, the solvent was removed by distillation under reducedpressure, and the resulting residue was purified by a columnchromatography (Wako Silica Gel C-200, eluent; chloroform:methanol=40:1by volume) to obtain 0.44 g (yield 64%) of1-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethylamino}-1-methylthio-2-nitroethenehaving a melting point of 69°-71° C.

(4) With 7.5 ml of ethanol were mixed 4.5 g of1-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethylamino}-1-methylthio-2-nitroetheneand 3.5 g of DL-[2-(3-bromophenyl)-2-hydroxyethyl]amine, and theresulting mixture was subjected to reaction at room temperature for 30hours. Thereto were added 5 ml of isopropanol and 30 ml of diethylether, and the mixture thus obtained was stirred, after which thecrystals formed were collected by filtration. The crystals wererecrystallized from 40 ml of isopropanol to obtain 4.3 g (yield 65%) ofN-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediaminehaving a melting point of 104°-106° C.

NMR (CDCl₃) δ values: 2.13 (9H, s, --CH₃ ×3), 2.6-3.0 (2H, m, >CH₂),3.15-3.7 (4H, m, >CH₂ ×2), 3.49 (2H, s, >CH₂), 3.94 (2H, s, >CH₂), 5.0(1H, m, ##STR236## 6.67 (1H, s, ═CH--), 6.79 (1H, s, thiophene ring H),7.25-7.85 (4H, m, benzene ring H×4).

EXAMPLE 5

(1) With 10 ml of ethanol was mixed 1.6 g of1-methylsulfinyl-1-methylthio-2-nitroethene, and 1.2 g of2-chloroethylamine hydrochloride was then added thereto, after which 1.0g of triethylamine was added dropwise at -20° C. in a nitrogenatmosphere. After they were subjected to reaction at the sametemperature for 2 hours and then gradually heated to room temperature.After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and 20 ml of ethyl acetate wasadded to the resulting residue, after which the resulting mixture waswashed with water and dried over anhydrous magnesium sulfate, and thesolvent was removed by distillation under reduced pressure to obtain 1.0g (yield 54.8%) of 1-(2-chloroethyl)amino-1-methylthio-2-nitroethenehaving a melting point of 115°-117° C.

(2) In 5 ml of methanol was dissolved 0.5 g of1-(2-chloroethyl)amino-1-methylthio-2-nitroethene obtained in above (1),and 0.55 g of DL-[2-hydroxy-2-(3-methoxyphenyl)ethyl]amine was addedthereto, after which the resulting mixture was allowed to stand at roomtemperature for 24 hours. The mixture was concentrated under reducedpressure, and 20 ml of ethyl acetate was added to the resulting residue,after which the thus obtained mixture was washed with 5% (by weight)hydrochloric acid and dried over anhydrous magnesium sulfate.Thereafter, the solvent was removed by distillation. The residue thusobtained was purified by a column chromatography (Wako Silica Gel C-200,eluent; chloroform:ethanol=20:1 by volume) to obtain 0.448 g (yield 52%)ofN-(2-chloroethyl)-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediaminehaving a melting point of 127°-130° C.

NMR (CDCl₃) δ values: 3.0-4.0 (6H, m, >CH₂ ×3), 3.77 (3H, s, --CH₃),4.6-5.2 (1H, m, ##STR237## 6.60 (1H, s, ═CH--), 6.4-7.8 (4H, m, benzenering H×4).

The following compound was obtained in the same manner as describedabove.

N-(2-chloroethyl)-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine

Melting point: 130°-131° C.

NMR (d₆ -DMSO) δ values: 2.98-3.88 (6H, m, >CH₂ ×3), 4.71 (1H, m,##STR238## 5.82 (1H, bs, --OH), 6.59 (1H, s, ═CH--), 7.36 (5H, s,benzene ring H×5), 10.34 (1H, bs, >NH).

(3) In a mixture of 1.2 ml of ethanol and 1.2 ml of water was dissolved0.3 g of 2-amidinothiomethyl-5-(dimethylamino)methyl-4-methylthiophenedihydrochloride, and 0.3 g ofN-(2-chloroethyl)-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediamineobtained in above (2) was added at one time at -10° C. in a nitrogenatmosphere, after which 1 ml of a 12% (by weight) aqueous sodiumhydroxide solution was added dropwise. After the addition, the resultingmixture was subjected to reaction at room temperature for 1 hour. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, and 5 ml of ethanol was added to the resultingresidue. The mixture thus obtained was stirred, after which theinsolubles were removed by filtration. The solvent was removed bydistillation under reduced pressure, and the resulting residue waspurified by a column chromatography (basic alumina, eluent:chloroform)to obtain 0.01 g (yield 2%) of oily N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediamine.

The physical property (NMR) of this compound was identical with that inExample 2.

(4) In 5 ml of methanol was dissolved 0.14 g of5-(dimethylamino)methyl-2-mercaptomethyl-4-methylthiophene, and 0.2 mlof a 3.57N sodium methoxide-methanol solution was added at roomtemperature in a nitrogen atomsphere, after which 0.2 g ofN-(2-chloroethyl)-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine wasadded at one time, after which the reaction mixture was allowed to standat room temperature for 24 hours, and the deposited substance wasremoved by filtration, after which the solvent was removed bydistillation under reduced pressure. Chloroform was added to theresulting residue, and the insolubles were removed by filtration, afterwhich the solvent was removed by distillation under reduced pressure,and the residue thus obtained was purified by a column chromatography(basic alumina, eluent; chloroform:methanol=10:1 by volume) to obtain0.033 g (yield 11%) ofN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-(.beta.-hydroxyphenethyl)-2-nitro-1,1-ethenediaminehaving a melting point of 114°-115° C.

The following compounds were obtained in the same manner as describedabove.

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methylphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]-methylthio]ethyl}-2-nitro-1,1-ethenediamine

The physical properties of these compounds were identical with those inExample 2.

EXAMPLE 6

(1) In 50 ml of anhydrous ethanol was suspended 9.3 g of1-methylsulfinyl-1-methylthio-2-nitroethene, and the resultingsuspension was stirred. A solution of 9.3 g ofDL-[2-hydroxy-2-(3-methylphenyl)ethyl]amine in 5 ml of ethanol was addedthereto dropwise at -10° C. to 0° C. over a period of 30 minutes in anitrogen atmosphere. After the addition, the resulting mixture wasstirred at the same temperature for 1.5 hours, and the crystalsdeposited were collected by filtration, washed with 10 ml of ethanol,and then dried to obtain 7.0 g (yield 50.8%) of1-{[2-hydroxy-2-(3-methylphenyl)ethyl]amino}-1-methylthio-2-nitroethenehaving a melting point of 99°-101° C.

NMR (CDCl₃) δ values: 2.38 (6H, s, --CH₃ ×2), 3.2-3.9 (2H, m, >CH₂), 4.3(1H, bs, --OH), 5.02 (1H, t, ##STR239## 6.62 (1H, s, ═CH--), 7.27 (4H,s, benzene ring H×4), 10.7 (1H, bs, >NH).

The following compounds were obtained in the same manner as describedabove.

1-{[2-(4-Fluorophenyl)-2-hydroxyethyl]amino}-1-methylthio-2-nitroethene

Melting point: 152°-154° C.

1-{[2-Hydroxy-2-(3-methoxyphenyl)ethyl]amino}-1-methylthio-2-nitroethene

Melting point: 148°-149.5° C.

(2) In 1 ml of dioxane were suspended 0.5 g of2-{[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio}ethylamine and0.5 g of1-{[2-hydroxy-2-(3-methylphenyl)ethyl]amino}-1-methylthio-2-nitroetheneobtained in above (1), and the resulting suspension was subjected toreaction at room temperature for 3 hours. After completion of thereaction, the solvent was removed by distillation under reducedpressure, and the obtained oily substance was purified by a columnchromatography (Wako Silica Gel C-200, eluent; chloroform:methanol=20:1by volume) to obtain 0.7 g (yield 80%) ofN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methylphenyl)ethyl]-2-nitro-1,1-ethenediaminehaving a melting point of 88°-89° C.

The physical property (NMR) of this product was identical with that inExample 2.

The following compounds were obtained in the same manner as describedabove.

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-(.beta.-hydroxyphenethyl)-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

The physical properties of these compounds were identical with those inExample 2.

EXAMPLE 7

(1) In 16 ml of N,N-dimethylformamide were dissolved 6.5 g of1-{[2-hydroxy-2-(3-methylphenyl)ethyl]amino}-1-methylthio-2-nitroethene,5.1 g of (tert.-butyl)dimethylsilyl chloride and 2.3 of imidazole, andthe resulting solution was subjected to reaction at room temperature for20 hours. After completion of the reaction, 100 ml of chloroform and 50ml of water were added thereto, and the organic layer was separated. Theorganic layer was washed with 50 ml of a saturated aqueous sodiumchloride solution and dried over anhydrous magnesium sulfate, afterwhich the solvent was removed by distillation under reduced pressure toobtain 9.0 g (yield 97%) of oily1-[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]amino-1-methylthio-2-nitroethene.

NMR (CDCl₃) δ values: -0.11 (3H, s, --CH₃), 0.09 (3H, s, --CH₃), 0.91(9H, s, --CH₃ ×3), 2.38 (3H, s, --CH₃), 2.42 (3H, s, --CH₃), 3.64 (2H,dd, >CH₂), 4.95 (1H, t, ##STR240## 6.67 (1H, s, ═CH--), 7.30 (4H, s,benzene ring H×4), 10.69 (1H, bs, >NH).

The following compound was obtained in the same manner as describedabove.

1-{[2-(Tert.-butyl)dimethylsilyoxy-2-(4-fluorophenyl)ethyl]amino}-1-methylthio-2-nitroethene

Melting point: 111°-113° C.

(2) In 10 ml of water was dissolved 4.4 g of silver nitrate, and 26 mlof a 1N aqueous sodium hydroxide solution was added with stirring,followed by adding thereto 1.2 g of ethyleneimine. A solution of 7.69 gof1-{[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]amino}-1-methylthio-2-nitroethenein 30 ml of chloroform was added dropwise at 25° C. to 30° C. over aperiod of 10 minutes. The resulting mixture was stirred at the sametemperature for 2 hours, after which the insolubles were removed byfiltration, and the organic layer was separated. The organic layer wasdried over anhydrous magnesium sulfate and concentrated, after which 25ml of n-hexane was added to the resulting residue, and the resultingmixture was stirred. The crystals deposited were collected by filtrationand dried to obtain 5.45 g (yield 81.3%) of1-aziridino-1-{[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]amino}-2-nitroethenehaving a melting point of 96°-98° C.

NMR (CDCl₃) δ values: -0.11 (3H, s, --CH₃), 0.10 (3H, s, --CH₃), 0.94(9H, s, --CH₃ ×3), 2.19 (4H, s, >CH₂ ×2), 2.38 (3H, s, --CH₃), 3.68 (2H,dd, >CH₂), 4.94 (1H, t, ##STR241## 6.56 (1H, s, ═CH--), 7.27 (4H, s,benzene ring H×4), 10.3 (1H, bs, >NH).

The following compound was obtained in the same manner as describedabove.

1-Aziridino-1-{[2-(tert.-butyl)dimethylsilyloxy-2-(4-fluorophenyl)ethyl]amino}-2-nitroethene

Melting point: 97°-99° C.

(3) A solution of 1.0 g of5-(dimethylamino)methyl-2-mercaptomethyl-4methylthiophene in 10 ml ofmethanol was added to 20 ml of methanol in a nitrogen atmosphere, and asolution of 1.74 g of1-aziridino-1-{[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]amino}-2-nitroetheneobtained in above (2) in 10 ml of methanol was then added dropwise atroom temperature over a period of 10 minutes. The resulting solution wassubjected to reaction with stirring at the same temperature for 1 hour.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure, and the resulting residue was purified by acolumn chromatography (Wako Silica Gel C-200, eluent;chloroform:ethanol=30:1 by volume) to obtain 2.24 g (yield 85.4%) ofoilyN-[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine.

NMR (CDCl₃) δ values: -0.10 (3H, s, --CH₃), 0.04 (3H, s, --CH₃), 0.99(9H, s, --CH₃ ×3), 2.13 (3H, s, --CH₃), 2.24 (6H, s, --CH₃ ×2), 2.35(3H, s, --CH₃), 2.74 (2H, t, >CH₂), 3.0-3.8 (4H, m, >CH₂ ×2), 3.51 (2H,s, >CH₂), 3.89 (2H, s, >CH₂), 4.93 (1H, t, ##STR242## 6.67 (1H, s,═CH--), 6.73 (1H, s, thiophene ring H), 7.24 (4H, s, benzene ring H×4),10.4 (1H, bs, >NH).

(4) In 10 ml of tetrahydrofuran was dissolved 0.93 g ofN-[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]-N'-{2-[[5-dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine,obtained in above (3), and 0.84 g of tetra(n-butyl)ammonium fluoride wasadded at 0° C. to 5° C., after which the resulting mixture was subjectedto reaction at the same temperature for 5 minutes and then at roomtemperature for 15 minutes. After completion of the reaction, thesolvent was removed by distillation under reduced pressure, and 10 ml ofwater and 10 ml of ethyl acetate were added to the resulting residue,after which the organic layer was separated. The organic layer waswashed with 10 ml of a saturated aqueous sodium chloride solution anddried over anhydrous magnesium sulfate, after which the solvent wasremoved by distillation under reduced pressure. The thus obtainedresidue was purified by a column chromatography (Wako Silica Gel C-200,eluent; chloroform:ethanol=20:1 by volume) to obtain 0.58 g (yield 78%)ofN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methylphenyl)ethyl]-2-nitro-1,1-ethenediaminehaving a melting point of 88°-89° C.

The physical property (NMR) of this product was identical with that inExample 2.

The following compounds were obtained in the same manner as describedabove.

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-(.beta.-hydroxyphenethyl)-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

The physical properties of these compounds were identical with those inExample 2.

EXAMPLE 8

(1) In a nitrogen stream, 4.6 g of sodium hydride (52% purity) wassuspended in 50 ml of N,N-dimethylformamide, and 7.7 g of cysteamine wasadded in small portions with stirring under ice-cooling. After theaddition, the resulting mixture was subjected to reaction at roomtemperature for 1 hour. To reaction mixture thus obtained was addeddropwise 7.58 ml of chloromethyl methyl ether with ice-cooling, andafter the addition, the resulting mixture was stirred at the sametemperature for 1 hour and then at room temperature for 30 minutes. Theinsolubles were removed by filtration and the thus obtainedN,N-dimethylformamide solution containing2-(methoxymethylthio)ethylamine was added dropwise to a solution of 25.0g of 1,1-bis(methylthio)-2-nitroethene in 100 ml of acetonitrile underreflux over a period of 45 minutes. After the addition, the resultingmixture was refluxed for 30 minutes, and the solvent was removed bydistillation under reduced pressure, after which 50 ml of ethanol wasadded to the resulting residue, and the thus obtained mixture wasstirred. The insolubles were removed by filtration and the solvent wasremoved by distillation under reduced pressure, after which theresulting residue was purified by a column chromatography (Wako SilicaGel C-200, eluent; benzene:ethyl acetate=10:1 by volume), and thecrystals thus obtained were washed with 30 ml of diisopropyl ether andthen dried to obtain 11.5 g (yield 48%) of1-methylthio-1-[2-(methoxymethylthio)ethylamino]-2-nitroethene having amelting point of 54°-58° C.

NMR (CDCl₃) δ values: 2.50 (3H, s, --CH₃), 2.92 (2H, t, >CH₂), 3.43 (3H,s, --OCH₃), 3.77 (2H, m, >CH₂), 4.74 (2H, s, >CH₂), 6.70 (1H, s, ═CH--),10.7 (1H, bs, >NH).

(2) With 15 ml of ethanol were mixed 7.5 g of the1-methylthio-1-[2-(methoxymethylthio)ethylamino]-2-nitroethene and 5.6 gof DL-β-hydroxyphenethylamine, and the resulting mixture was stirred atroom temperature for 8 hours, and then allowed to stand overnight atroom temperature. The solvent was removed by distillation under reducedpressure, and the crystals thus obtained were washed with 15 ml ofisopropanol and then dried to obtain 7.3 g (yield 71%) ofN-(β-hydroxyphenethyl)-N'-[2-(methoxymethylthio)ethyl]-2-nitro-1,1-ethenediaminehaving a melting point of 107°-109.5° C.

NMR (CDCl₃) δ values: 2.76 (2H, t, >CH₂), 3.1-3.7 (4H, m, >CH₂ ×2), 3.30(3H, s, --OCH₃), 4.59 (2H, s, >CH₂), 4.9 (1H, m, ##STR243## 6.60 (1H, s,═CH--), 7.38 (5H, s, benzene ring H×5).

(3) With 5 ml of anhydrous methylene chloride was mixed 1.45 ml of aboron trifluoride-acetic acid complex compound [containing about 40% (byweight) of boron trifluoride], and a solution of 0.46 g of2-(dimethylamino)methyl-3-methylthiophene and 1.2 g of theN-(β-hydroxyphenethyl)-N'-[2-(methoxymethylthio)ethyl]-2-nitro-1,1-ethenediamineobtained in above (2) in 10 ml of anhydrous methylene chloride was addeddropwise thereto at 10° to 13° C. over a period of 30 minutes. After theaddition, the resulting mixture was stirred at room temperature for 40minutes, and the solution thus obtained was added to 10 ml of ice water,followed by adding thereto 20 ml of chloroform. The resulting mixturewas adjusted to pH 9 to 10 with anhydrous potassium carbonate, and theinsolubles were removed by filtration. The organic layer was separatedand then extracted with 18 ml of 0.5N hydrochloric acid, after which theextract was adjusted to pH 9 to 10 with anhydrous potassium carbonate,and extracted with 30 ml of chloroform. The thus obtained organic layerwas washed with 10 ml of a saturated aqueous sodium chloride solution,and the solvent was removed by distillation under reduced pressure,after which the resulting residue was purified by a columnchromatography (Wako Silica Gel C-200, eluent; chloroform:ethanol=20:1by volume), and crystallized from an isopropanol-diethyl ether solutionto obtain 0.14 g (yield 10%) ofN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-(.beta.-hydroxyphenethyl)-2-nitro-1,1-ethenediaminehaving a melting point of 114°-115° C.

The physical property (NMR) of this product was identical with that inExample 2.

The following compounds were obtained in the same manner as describedabove.

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methylphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]-methylthio]ethyl}-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

The physical properties of these compounds were identical with those inExample 2.

EXAMPLE 9

In a mixed solvent of 20 ml of methylene chloride and 10 ml of methanolwas dissolved 2.4 g of 5-(3-methoxyphenyl)-2-nitromethyleneoxazolidineat room temperature, and a solution of 2.0 g of5-(dimethylamino)methyl-2-mercaptomethyl-4-methylthiophene in 5 ml ofmethanol was added thereto in a nitrogen atmosphere. Then, the solutionof 0.5 g of ethyleneimine in 5 ml of methanol was added dropwise at thesame temperature over a period of 10 minutes. After addition, theresulting solution was subjected to reaction with stirring for 5 hours.After the completion of the reaction, the solvent was removed bydistillation under reduced pressure, and the residue obtained waspurified by a column chromatography (Wako Silica Gel C-200, eluent;chloroform:ethanol=30:1 by volume) to obtain 4.0 g (yield 83.5%) of oilyN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(3-methoxyphenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine.

The physical property (NMR) of this product was identical with that inExample 2.

The following compounds were obtained in the same manner as describedabove.

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-(.beta.-hydroxyphenethyl)-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methylphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-bromophenyl)-2-hydroxyethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine

N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-trifluoromethylphenyl)ethyl]-2-nitro-1,1-ethenediamine

N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N'-2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]-methylthio]ethyl}-2-nitro-1,1-ethenediamine

The physical properties of these compounds were identical with those inExample 2.

EXAMPLE 10

(1) In 150 ml of N,N-dimethylformamide was suspended 4.8 g of sodiumhydride (52% purity), and 20.0 g of 3-piperidinomethylphenol was addedin small portions with stirring under ice-cooling. After the addition,the resulting mixture was subjected to reaction at room temperature for1 hour. To the reaction mixture thus obtained was added 28.0 g ofN-(3-bromopropyl)phthalimide, and the resulting mixture was subjected toreaction for 24 hours. After completion of the reaction, the solvent wasremoved by distillation under reduced pressure, and 300 ml of water and300 ml of chloroform were added to the resulting residue to dissolve thesame. The organic layer was separated and then dried over anhydrousmagnesium sulfate, after which the solvent was removed by distillationunder reduced pressure to obtain 35.0 g (yield 88.5%) of oilyN-[3-(3-piperidinomethylphenoxy)propyl]phthalimide.

(2) In 200 ml of ethanol was dissolved 29.3 g of theN-[3-(3-piperidinomethylphenoxy)propyl]phthalimide obtained in above(1), and 23.1 ml of hydrazine hydrate was added with stirring at roomtemperature, after which the resulting mixture was subjected to reactionat the same temperature for 24 hours. After completion of the reaction,the solvent was removed by distillation under reduced pressure, and 300ml of toluene was added to the resulting residue, after which azeotropicdehydration was carried out. Thereafter, 500 ml of chloroform was added,and the insolubles were removed by filtration. The solvent was removedby distillation under reduced pressure to obtain 16.1 g (yield 84%) ofoily 3-(3-piperidinomethylphenoxy)propylamine.

(3) With 100 ml of acetonitrile were mixed 16.0 g of the3-(3-piperidinomethylphenoxy)propylamine obtained in above (2) and 21.3g of 1,1-bis(methylthio)-2-nitroethene, and the resulting mixture wassubjected to reaction under reflux for 2 hours. After completion of thereaction, the solvent was removed by distillation under reducedpressure, and 100 ml of ethanol was added to the resulting residue,after which the insolubles were removed by filtration. The solvent wasremoved by distillation under reduced pressure, and the resultingresidue was purified by a column chromatography (Wako Silica Gel C-200,eluent chloroform:methanol=20:1 by volume) to obtain 18.0 g (yield76.3%) of1-methylthio-2-nitro-1-[3-(3-piperidinomethylphenoxy)propylamino]ethenehaving a melting point of 68°-69.5° C.

NMR (CDCl₃) δ values: 1.16-1.83 (6H, m, >CH₂ ×3), 1.89-2.53 (6H, m, >CH₂×3), 2.42 (3H, s, --SCH₃), 3.47 (2H, s, >CH₂), 3.69 (2H, td, >CH₂), 4.11(2H, t, >CH₂), 6.62 (1H, s, =CH--), 6.75-7.43 (4H, m, benzene ring H×4),10.61 (1H, bs, >NH).

(4) In 43 ml of ethanol were dissolved 8.5 g of the1-methylthio-2-nitro-1-[3-(3-piperidinomethylphenoxy)propylamino]etheneobtained in above (3) and 10.8 g ofDL-[2-(4-fluorophenyl)-2-hydroxyethyl]amine, and the resulting solutionwas subjected to reaction under reflux for 2 hours. After completion ofthe reaction, the solvent was removed by distillation under reducedpressure, and the resulting residue was purified by a columnchromatography (Wako Silica Gel C-200, eluent; chloroform:methanol=10:1by volume) to obtain 8.03 g (yield 73%) ofN-[2-(4-fluorophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediaminehaving a melting point of 135°-136° C.

Elementary analysis values (for C₂₅ H₃₃ FN₄ O₄) Calculated (%): C;63.54, H; 7.04, N; 11.86. Found (%): C; 63.80, H; 7.33, N; 11.78.

The compounds listed in Table 11 were obtained in the same manner asdescribed above.

                  TABLE 11                                                        ______________________________________                                         ##STR244##                                                                   R.sup.2         Physical properties                                           ______________________________________                                         ##STR245##                                                                                    ##STR246##                                                   Oily                                                                                           ##STR247##                                                                    ##STR248##                                                                    ##STR249##                                                                    ##STR250##                                                                    ##STR251##                                                                   6.8-7.7 (9H, m, benzene ring                                                   ##STR252##                                                    ##STR253##                                                                                    ##STR254##                                                   Oily                                                                                           ##STR255##                                                                    ##STR256##                                                                   3.88 (3H, s, CH.sub.3), 4.11 (2H, m,                                           ##STR257##                                                                    ##STR258##                                                                   6.62-7.75 (9H, m, CH, benzene                                                  ##STR259##                                                    ##STR260##                                                                                    ##STR261##                                                   Oily                                                                                           ##STR262##                                                                    ##STR263##                                                                   3.76 (3H, s, CH.sub.3),                                                        ##STR264##                                                                    ##STR265##                                                                   (1H, s, CH), 6.69-7.45 (8H, m,                                                benzene ring H × 8), 10.38 (1H,                                          ##STR266##                                                    ##STR267##                                                                                    ##STR268##                                                   Oily                                                                                           ##STR269##                                                                    ##STR270##                                                                    ##STR271##                                                                    ##STR272##                                                                   6.66-7.85 (7H, m, benzene ring                                                H × 7)                                                   ##STR273##     Melting point: 163-164° C.                              ##STR274##     Melting point: 135-139° C.                              ##STR275##     Melting point: 133-134° C.                              ##STR276##                                                                                    ##STR277##                                                   Oily                                                                                           ##STR278##                                                                    ##STR279##                                                                    ##STR280##                                                                    ##STR281##                                                                   6.64-7.34 (8H, m, benzene ring                                                 ##STR282##                                                    ##STR283##                                                                                    ##STR284##                                                   Oily                                                                                           ##STR285##                                                                    ##STR286##                                                                    ##STR287##                                                                    ##STR288##                                                                   6.7-7.4 (7H, m, benzene ring                                                  H × 4, thiophene ring H × 3)                       ##STR289##                                                                                    ##STR290##                                                   Oily                                                                                           ##STR291##                                                                    ##STR292##                                                                    ##STR293##                                                                    ##STR294##                                                                   H × 2), 6.58 (1H, s, CH),                                               6.65-7.74 (5H, m, benzene ring                                                H × 4, furan ring H), 10.38 (1H,                                         ##STR295##                                                    ##STR296##                                                                                    ##STR297##                                                   Oily                                                                                           ##STR298##                                                                    ##STR299##                                                                    ##STR300##                                                                    ##STR301##                                                                   6.80-7.58 (8H, m, benzene ring                                                 ##STR302##                                                    ##STR303##                                                                                    ##STR304##                                                   Oily                                                                                           ##STR305##                                                                    ##STR306##                                                                   3.80 (3H, s, CH.sub.3), 4.10 (2H, m,                                           ##STR307##                                                                   5.20 (1H, bs, OH),                                                            6.70 (1H, s, CH),                                                             6.75-7.58 (8H, m, benzene ring                                                 ##STR308##                                                    ##STR309##                                                                                    ##STR310##                                                   Oily                                                                                           ##STR311##                                                                   2.35 (3H, s, CH.sub.3), 3.04-3.71                                              ##STR312##                                                                    ##STR313##                                                                    ##STR314##                                                                   (1H, s, CH), 6.72-7.48 (8H, m,                                                benzene ring H × 8), 10.45 (1H,                                          ##STR315##                                                    ##STR316##                                                                                    ##STR317##                                                   Oily                                                                                           ##STR318##                                                                    ##STR319##                                                                    ##STR320##                                                                    ##STR321##                                                                    ##STR322##                                                                   6.60-7.30 (7H, m, benzene ring                                                H × 7)                                                   ##STR323##                                                                                    ##STR324##                                                   Oily                                                                                           ##STR325##                                                                    ##STR326##                                                                    ##STR327##                                                                    ##STR328##                                                                   OCH.sub.2 O), 6.60 (1H, s,                                                    CH), 6.65-7.42 (7H, m,                                                        benzene ring H × 7), 9.90-10.40                                          ##STR329##                                                    ##STR330##                                                                                    ##STR331##                                                   Oily                                                                                           ##STR332##                                                                    ##STR333##                                                                    ##STR334##                                                                    ##STR335##                                                                   CH), 6.70-7.52                                                                (8H, m, benzene ring H × 8)                              ##STR336##                                                                                    ##STR337##                                                   Oily                                                                                           ##STR338##                                                                    ##STR339##                                                                    ##STR340##                                                                   6.78-7.51 (8H, m, benzene ring                                                H × 8)                                                   ##STR341##                                                                                    ##STR342##                                                   Oily                                                                                           ##STR343##                                                                    ##STR344##                                                                    ##STR345##                                                                    ##STR346##                                                                   6.81-7.47 (5H, m, benzene ring                                                H × 4, pyridine ring H),                                                7.60-8.01 (1H, m, pyridine ring H),                                           8.31-8.71 (2H, m, pyridine ring                                                ##STR347##                                                    ##STR348##                                                                                    ##STR349##                                                   Oily                                                                                           ##STR350##                                                                    ##STR351##                                                                    ##STR352##                                                                    ##STR353##                                                                   6.73-7.47 (8H, m, benzene ring                                                H × 8)                                                   ##STR354##                                                                                    ##STR355##                                                   Oily                                                                                           ##STR356##                                                                   2.30 (3H, s, CH.sub.3), 3.10-3.70                                              ##STR357##                                                                    ##STR358##                                                                   6.68 (1H, s, CH), 6.75-7.76 (8H,                                              m, benzene ring H × 8)                                   ##STR359##                                                                                    ##STR360##                                                   Oily                                                                                           ##STR361##                                                                   2.17 (3H, s,  CH.sub.3), 3.03-3.83                                             ##STR362##                                                                    ##STR363##                                                                   6.69 (1H, s, CH), 6.75-7.50                                                   (6H, m, benzene ring H × 4,                                             thiophene ring H × 2)                                    ##STR364##                                                                                    ##STR365##                                                   Oily                                                                                           ##STR366##                                                                    ##STR367##                                                                    ##STR368##                                                                    ##STR369##                                                                   bs, OH), 6.68 (1H, s, CH),                                                    6.75- 7.46 (8H, m, benzene ring                                               H × 8)                                                   ##STR370##                                                                                    ##STR371##                                                   Oily                                                                                           ##STR372##                                                                    ##STR373##                                                                    ##STR374##                                                                    ##STR375##                                                                   6.70-8.31 (8H, m, benzene ring                                                H × 8)                                                   ##STR376##                                                                                    ##STR377##                                                   Oily                                                                                           ##STR378##                                                                    ##STR379##                                                                    ##STR380##                                                                    ##STR381##                                                                   CH), 6.85-7.85                                                                (8H, m, benzene ring H × 8)                              ##STR382##                                                                                    ##STR383##                                                   Oily                                                                                           ##STR384##                                                                    ##STR385##                                                                    ##STR386##                                                                    ##STR387##                                                                   6.54-7.45 (9H, m, CH, benzene                                                 ring H × 8)                                              ##STR388##                                                                                    ##STR389##                                                   Amorphous                                                                                      ##STR390##                                                                    ##STR391##                                                                    ##STR392##                                                                    ##STR393##                                                                   CH), 6.80-8.20 (10H, m,                                                       benzene ring H × 8, NH.sub.2),                                           ##STR394##                                                    ##STR395##                                                                                    ##STR396##                                                   Amorphous                                                                                      ##STR397##                                                                   2.95 (6H, s, CH.sub.3 × 2), 3.00-3.80                                    ##STR398##                                                                   3.90-4.35 (2H, m,                                                              ##STR399##                                                                    ##STR400##                                                                   6.40-7.70 (8H, m, benzene ring                                                H × 8)                                                   ##STR401##                                                                                    ##STR402##                                                   Oily                                                                                           ##STR403##                                                                   2.42 (3H, s, SCH.sub.3), 3.0-3.8                                               ##STR404##                                                                    ##STR405##                                                                   (1H, s, CH), 6.75-7.60 (8H, m,                                                benzene ring H × 8), 10.35 (1H,                                          ##STR406##                                                    ##STR407##                                                                                    ##STR408##                                                   Amorphous                                                                                      ##STR409##                                                                    ##STR410##                                                                   3.05-3.85 (6H, m,                                                              ##STR411##                                                                    ##STR412##                                                                   CH), 6.75-7.80 (8H, m,                                                        benzene ring H × 8),                                                     ##STR413##                                                    ##STR414##     Melting point: 111-112.5° C.                            ##STR415##                                                                                    ##STR416##                                                   Oily                                                                                           ##STR417##                                                                    ##STR418##                                                                    ##STR419##                                                                    ##STR420##                                                                   6.75-7.85 (8H, m, benzene ring                                                 ##STR421##                                                    ##STR422##                                                                                    ##STR423##                                                   Amorphous                                                                                      ##STR424##                                                                    ##STR425##                                                                   3.81 (6H, s, OCH.sub.3 × 2),                                             ##STR426##                                                                    ##STR427##                                                                   6.58 (1H, s, CH),                                                             6.40-7.50 (7H, m, benzene ring                                                 ##STR428##                                                    ##STR429##                                                                                    ##STR430##                                                   Oily                                                                                           ##STR431##                                                                    ##STR432##                                                                    ##STR433##                                                                    ##STR434##                                                                   OH), 6.65 (1H, s, CH),                                                        6.74-7.45 (7H, m, benzene ring                                                 ##STR435##                                                   ______________________________________                                    

EXAMPLE 11

In 10 ml of methylene chloride was dissolved 0.68 g ofN,N'-carbonyldiimidazole, and 5 ml of a methylene chloride solutioncontaining 1.0 g of 3-(3-piperidinomethylphenoxy)propylamine was addeddropwise at 0° C. to 5° C., after which the resulting mixture wassubjected to reaction at the same temperature for 1 hour and then atroom temperature for 1 hour. Subsequently, 0.6 g ofDL-β-hydroxyphenethylamine was added at 0° C., and the mixture thusobtained was subjected to reaction with ice-cooling for 1 hour and thenat room temperature for 1 hour. After completion of the reaction, 10 mlof water was added, and the organic layer was separated. The organiclayer was dried over anhydrous magnesium sulfate, after which thesolvent was removed by distillation under reduced pressure, and theresulting residue was purified by a column chromatography (Wako SilicaGel C-200, eluent; chloroform:ethanol=20:1 by volume) to obtain 0.75 g(yield 45.6%) of oily N-(β-hydroxyphenethyl)-N'-[3-(3-piperidinomethylphenoxy)propyl]urea.

NMR (CDCl₃) δ values: 1.28-1.68 (6H, m, >CH₂ ×3), 1.69-2.54 (6H, m, >CH₂×3), 2.96-3.54 (6H, m, >CH₂ ×3), 3.97 (2H, m, >CH₂), 4.74 (1H, m,##STR436## 4.20-5.30 (1H, b, --OH), 6.00 (2H, bs, >NH×2), 6.63-7.68 (9H,m, benzene ring H×9).

EXAMPLE 12

(1)

In 900 ml of methanol were dissolved 30 g of2-[(2-guanidino-4-thiazolyl)methylthio]ethylamine dihydrochloride and27.4 ml of triethylamine, and 15.1 g of dimethylcyanoimidedithiocarbonate was added at room temperature, and the resulting mixturewas subjected to reaction overnight at the same temperature. Aftercompletion of the reaction, the solvent was removed by distillationunder reduced pressure, and 400 ml of ethyl acetate and 300 ml of waterwere added to the resulting residue, after which the white crystalsdeposited were collected by filtration and dried to obtain 27 g (yield83%) ofN-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-S-methylisothioureahaving a melting point of 127°-134° C.

IR (KBr) cm⁻¹ : ν_(C).tbd.N 2160.

NMR (d₆ -DMSO) δ values: 2.50-3.00 (5H, m, --CH₃, >CH₂), 3.10-4.10 (4H,m, >CH₂ ×2), 6.86 (1H, s, thiazole ring H), 7.70 (4H, bs, --NH₂ ×2).

(2) With 5 ml of ethanol were mixed 1.5 g of theN-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-S-methylisothioureaobtained in above (1) and 3.1 g of DL-β-hydroxyphenethylamine, and theresulting mixture was subjected to reaction under reflux for 4 hours.After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and the resulting residue waswashed with two 20-ml portions of diethyl ether. The residue was thendissolved in 5 ml of acetone, and a solution of 1.5 g of maleic acid in8 ml of acetone was added at room temperature. Subsequently, 10 ml ofdiethyl ether was added dropwise, after which the crystals depositedwere collected by filtration and recrystallized from isopropanol toobtain 1.73 g (yield 71%) of maleic acid salt (1:1 adduct) ofN-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N"-(β-hydroxyphenethyl)guanidinehaving a melting point of 100°-103° C.

IR (KBr) cm⁻¹ : ν_(C).tbd.N 2160.

The following compound was obtained in the same manner as describedabove.

Maleic acid salt (1:1 adduct) ofN-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N"-(2-methoxy-2-phenylethyl)guanidine

Melting point: 136°-138° C.

IR (KBr) cm⁻¹ : ν_(C).tbd.N 2170.

EXAMPLE 13

With 5 ml of ethanol were mixed 1.0 g ofN-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-S-methylisothiourea,1.38 g of DL-(2-hydroxy-1-methyl-2-phenylethyl)amine and 0.57 g ofsilver nitrate, and the resulting mixture was subjected to reactionunder reflux for 2 hours and 20 minutes. After completion of thereaction, the insolubles were removed by filtration, and the solvent wasremoved by distillation under reduced pressure. The resulting residuewas purified by a column chromatography (Florisil, eluent;chloroform:ethanol=9:1 by volume). The amorphous solid thus obtained wasdissolved in 4 ml of acetone, and a solution of 1 g of maleic acid in 8ml of acetone was added at room temperature. Subsequently, 10 ml ofdiethyl ether was added dropwise, after which the crystals depositedwere collected by filtration and recrystallized from isopropanol toobtain 1.0 g (yield 59%) of maleic acid salt (1:1 adduct) ofN-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N"-(2-hydroxy-1-methyl-2-phenylethyl)guanidinehaving a melting point of 125.5°-127° C.

IR (KBr) cm⁻¹ : ν_(C).tbd.N 2160.

EXAMPLE 14

With 15 ml of ethanol were mixed 3.0 g ofN-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-S-methylisothiourea,4.9 g of DL-[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amine and 1.97 g ofsilver nitrate, and the resulting mixture was subjected to reactionunder reflux for 1.5 hours. After completion of the reaction, theinsolubles were removed by filtration, and the solvent was removed bydistillation under reduced pressure. The resulting residue was purifiedby a column chromatography (Wako Silica Gel C-200, eluent;chloroform:methanol=5:1 by volume) and crystallized from methanol toobtain 2.5 g (yield 68%) ofN-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N"-[2-hydroxy-2-(3-hydroxyphenyl)ethyl]guanidinehaving a melting point of 162°-164° C.

IR (KBr) cm⁻¹ : ν_(C).tbd.N 2160.

The following compound was obtained in the same manner as describedabove.

N-cyano-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N"-[2-hydroxy-2-4-nitrophenyl)ethyl]guanidine(amorphous)

IR (KBr) cm⁻¹ : ν_(C).tbd.N 2160.

NMR (d₆ -DMSO) δ values: 2.33-2.90 (2H, m, >CH₂), 2.95-3.60 (4H, m, >CH₂×2), 3.79 (2H, s, >CH₂), 4.91 (1H, m, ##STR437## 6.54-7.37 (2H,m, >NH×2), 7.07 (1H, s, thiazole ring H), 7.61, 8.17 (4H, AA', BB',benzene ring H×4), 8.29 (4H, bs, --NH₂ ×2).

EXAMPLE 15

(1) In 300 ml of methanol was suspended 20 g of2-[(2-guanidino-4-thiazolyl)methylthio]ethylamine dihydrochloride, and7.1 g of sodium methoxide (99.7% purity) was added, after which thecrystals deposited were removed by filtration and the solvent wasremoved by distillation under reduced pressure. With the resultingresidue were mixed 150 ml of ethanol, 80 ml of acetonitrile and 23.9 gof 1,1-bis(methylthio)-2-nitroethene, and the resulting mixture wassubjected to reaction under reflux for 5 hours. After completion of thereaction, the reaction mixture was cooled with ice, and the crystalsdeposited were collected by filtration and extracted with 500 ml ofmethanol with heating. The extract was concentrated to dryness underreduced pressure, and the crystals thus obtained were washed with 100 mlof acetonitrile to obtain 14.8 g (yield 65%) of1-{2-[(2-guanidino-4-thiazolyl)methylthio]ethylamino}-1-methylthio-2-nitroethenehaving a melting point of 154°-156° C. (decomp.).

NMR (d₆ -DMSO) δ values: 2.67 (3H, s, --CH₃), 2.20-3.15 (2H, m, >CH₂),3.15-4.15 (4H, m, >CH₂ ×2), 6.77 (1H, s, ═CH--), 6.87 (1H, s, thiazolering H), 7.67 (4H, bs, --NH₂ ×2).

(2) With 60 ml of ethanol were mixed 2.0 g of the1-{2-[(2-guanidino-4-thiazolyl)methylthio]ethylamino}-1-methylthio-2-nitroetheneobtained in above (1) and 3.9 g of DL-β-hydroxyphenethylamine, and theresulting mixture was subjected to reaction under reflux for 2 hours.After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and the oily substance thusobtained was washed with two 40-ml portions of diethyl ether and thenpurified by a column chromatography (Wako Silica Gel C-200, eluent;chloroform:methanol=9:1 by volume) to obtain 1.0 g (yield 40%) ofamorphousN-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine.

NMR (d₆ -DMSO) δ values: 2.50-3.00 (2H, m, >CH₂), 3.20-3.65 (4H, m, >CH₂×2), 3.75 (2H, s, >CH₂), 4.91 (1H, m, ##STR438## 6.69 (1H, s, thiazolering H), 6.75 (1H, s, ═CH--), 7.03 (4H, bs, --NH₂ ×2), 7.65 (5H, s,benzene ring H×5), 7.3-7.8 (2H, m, >NH×2).

The following compounds were obtained in the same manner as describedabove.

N-[2-(4-chlorophenyl)-2-hydroxyethyl]-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-2-nitro-1,1-ethenediamine

Melting point: 146°-150° C. (decomp.).

N-[2-(2-furyl)-2-hydroxyethyl]-N'-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-2-nitro-1,1-ethenediamine

Melting point: 171°-173° C. (decomp.).

N-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N'-[2-hydroxy-2-(2-thienyl)ethyl]-2-nitro-1,1-ethenediamine

Melting point: 181°-183° C. (decomp.).

N-{2-[(2-guanidino-4-thiazolyl)methylthio]ethyl}-N'-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-2-nitro-1,1-ethenediamine(amorphous)

NMR (d₆ -DMSO) δ values: 2.50-3.00 (2H, m, >CH₂), 3.15-3.95 (4H, m, >CH₂×2), 3.75 (2H, bs, >CH₂), 4.76 (1H, m, ##STR439## 6.66 (1H, s, ═CH--),6.75 (1H, s, thiazole ring H), 6.86, 7.32 (4H, AA', BB', benzene ringH×4), 6.60-7.90 (4H, bs, --NH₂ ×2).

EXAMPLE 16

With 5 ml of ethanol were mixed 1 g ofN-cyano-N'-{2-[(5-methyl-4-imidazolyl)methylthio]ethyl}-S-methylisothioureaand 2.6 g of DL-β-hydroxyphenethylamine, and the resulting mixture wassubjected to reaction under reflux for 5 hours. After completion of thereaction, the solvent was removed by distillation under reducedpressure, and the oily substance thus obtained was washed with 20 ml ofdiethyl ether and then purified by a column chromatography (Wako SilicaGel C-200, eluent; chloroform:methanol=10:1 by volume) to obtain 0.27 g(yield 20%) of amorphousN-cyano-N'-(β-hydroxyphenethyl)-N"-{2-[(5-methyl-4-imidazolyl)methylthio]ethyl}guanidine.

NMR (d₆ -DMSO) δ values: 2.16 (3H, s, --CH₃), 2.40-2.90 (2H, m, >CH₂),3.05-3.95 (4H, m, >CH₂ ×2), 3.67 (2H, bs, >CH₂), 4.83 (1H, m, ##STR440##6.79 (3H, bs, >NH×3), 7.38 (5H, bs, benzene ring H×5), 7.52 (1H, s,imidazole ring H).

EXAMPLE 17

In 15 ml of pyridine was dissolved 1.0 g ofN-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-N'-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-2-nitro-1,1-ethenediamine,and 0.86 ml of acetic anhydride was added with ice-cooling, after whichthe resulting mixture was subjected to reaction at room temperature for4 hours. After completion of the reaction, the solvent was removed bydistillation under reduced pressure, and 20 ml of chloroform and 10 mlof water were added to the residue to dissolve the same. The aqueouslayer was adjusted to pH 10 with a 1N aqueous sodium hydroxide solution,after which the chloroform layer was separated and then washed withwater. After the chloroform layer was dried over anhydrous magnesiumsulfate, the solvent was removed by distillation under reduced pressure,and the resulting residue was purified by a column chromatography (WakoSilica Gel C-200, eluent; chloroform:methanol=20:1 by volume) to obtain0.65 g (yield 54.6%) of amorphousN-[2-acetoxy-2-(4-acetoxyphenyl)ethyl]-N'-{2-[[5-(dimethylamino)methyl-2-furyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine.

NMR (CDCl₃) δ values: 2.08 (3H, s, --CH₃), 2.26 (9H, s, --CH₃ ×3),2.47-2.92 (2H, m, >CH₂), 3.10-3.87 (4H, m, >CH₂ ×2), 3.55 (2H, s, >CH₂),3.73 (2H, s, >CH₂), 5.98 (1H, t, ##STR441## 6.20 (2H, s, furan ringH×2), 6.66 (1H, s, ═CH--), 7.10, 7.47 (4H, AA', BB', benzene ring H×4),8.87 (1H, bs, >NH).

EXAMPLE 18

In 2 ml of ethanol was dissolved 0.18 g ofN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediamine,and a solution of 0.052 g of oxalic acid dihydrate in 1 ml of ethanolwas added thereto. After deposition of an oxalic acid salt, 2 ml ofdiethyl ether was added, and the oxalic acid salt was collected byfiltration to obtain 0.18 g of the oxalic acid salt ofN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-2-nitro-1,1-ethenediaminehaving a melting point of 114°-116° C. (decomp.).

EXAMPLE 19

With 15 ml of ethanol was mixed 0.8 g ofN-[2-hydroxy-2-(4-nitrophenyl)ethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine,and hydrogen gas was introduced thereinto in the presence of 0.1 g of 5%(by weight) palladium carbon at ordinary temperature and underatmospheric pressure for 7 hours until the absorption of hydrogen gasceased. Subsequently, the catalyst was removed by filtration and thesolvent was removed by distillation under reduced pressure. Theresulting residue was purified by a column chromatography (Wako SilicaGel C-200, eluent; chloroform:methanol=5:1 by volume) to obtain 0.3 g(yield 40%) of amorphousN-[2-(4-aminophenyl)-2-hydroxyethyl]-2-nitro-N'-[3-(3-piperidinomethylphenoxy)propyl]-1,1-ethenediamine.

NMR (CDCl₃) δ values: 1.10-1.70 (6H, m, >CH₂ ×3), 1.80-2.60 (6H, m, >CH₂×3), 3.10-3.60 (6H, m, >CH₂ ×3), 4.00 (2H, m, >CH₂), 4.20-5.00 (4H, m,--NH₂ ##STR442## --OH), 6.40-7.40 (9H, m, ═CH--, benzene ring H×8).

EXAMPLE 20

The compounds listed in Tables 12 and 13 were obtained by effectingreaction by use of the corresponding starting materials in the samemanner as in Examples 1, 2 and 9. (Unless otherwise specified, as thecompounds of the formula (V), their DL-forms were used.)

                                      TABLE 12                                    __________________________________________________________________________     ##STR443##                                                                   R.sup.1        Z        Y    R.sup.2   Physical Properties                    __________________________________________________________________________     ##STR444##    NSO.sub.2 CH.sub.3                                                                     CH.sub.2                                                                            ##STR445##                                                                              ##STR446##                             ##STR447##    NSO.sub.2 CH.sub.3                                                                     CH.sub.2                                                                            ##STR448##                                                                              ##STR449##                             ##STR450##                                                                                   ##STR451##                                                                            CH.sub.2                                                                            ##STR452##                                                                              ##STR453##                             ##STR454##    NCN      CH.sub.2                                                                            ##STR455##                                                                              ##STR456##                             ##STR457##    CHNO.sub.2                                                                              ##STR458##                                                                         ##STR459##                                                                              ##STR460##                             ##STR461##    CHNO.sub.2                                                                             CH.sub.2                                                                            ##STR462##                                                                              ##STR463##                             ##STR464##    CHNO.sub.2                                                                             CH.sub.2                                                                            ##STR465##                                                                              ##STR466##                             ##STR467##    CHNO.sub.2                                                                             CH.sub.2                                                                            ##STR468##                                                                              ##STR469##                             ##STR470##    CHNO.sub.2                                                                             CH.sub.2                                                                            ##STR471##                                                                             Melting point: 115-118° C.       ##STR472##    CHNO.sub.2                                                                             CH.sub.2                                                                            ##STR473##                                                                             *1 Melting point: 128-139°                                             C. [α].sub.D.sup.24 =                                                   -26.9° (C 0.962, 0.1NHCl)        ##STR474##    CHNO.sub.2                                                                             CH.sub.2                                                                            ##STR475##                                                                             *2 Melting point: 128-130°                                             C. [α].sub.D.sup.23 =                                                   +26.8° (C 0.99, 0.1NHCl)         ##STR476##    CHNO.sub.2                                                                             CH.sub.2                                                                            ##STR477##                                                                             *3 Amorphous [α].sub.D.sup.20                                            = +12.7° (C 0.52, CH.sub.3                                            OH)                                     ##STR478##    CHNO.sub.2                                                                             CH.sub.2                                                                            ##STR479##                                                                             *4 Amorphous [α].sub.D.sup.24                                            = -11.7° (C 0.562,                                                    CH.sub.3 OH)                            ##STR480##    CHNO.sub. 2                                                                            CH.sub.2                                                                            ##STR481##                                                                             *5 Oily [α].sub.D.sup.20 =                                              +17.4° (C 0.472, CH.sub.3                                              OH)                                     ##STR482##    CHNO.sub.2                                                                             CH.sub.2                                                                            ##STR483##                                                                             *6 Oily [α].sub.D.sup.24 =                                              -17.7° (C 0.514, CH.sub.3       __________________________________________________________________________                                           OH                                      (1) *1: R(-) configuration obtained by using                                  R(-)[2-hydroxy-2-(4-hydroxyphenyl)-ethyl]amine {[α].sub.D.sup.25 =      -49.1° (C 1.00, 0.1NHCl): 88% optical                                  (2) *2: S(+) configuration obtained by using                                  S(+)[2-hydroxy-2-(4-hydroxyphenyl)-ethyl]amine {[α].sub.D.sup.23 =      +51.5° (C 1.01, 0.1NHCl): 98% optical                                  (3) *3: R(+) configuration obtained by using hydrochloride salt of            R(+)[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amine {[α].sub.D.sup.22 = +     53.4° (C 0.494, CH.sub.3 OH)}-                                         (4) *4: S(-) configuration obtained by using hydrochloride salt of            S(-)[2-hydroxy-2-(3-hydroxyphenyl)ethyl]amine {[α.sub.D.sup.19 =        -47.3° (C 0.48, CH.sub.3 OH)}-                                         (5) *5: R(+) configuration obtained by using hydrochloride salt of            R(+)[2-hydroxy-2-(3-methoxyphenyl)ethyl]amine {[α].sub.D.sup.21 =       +52.6° (C 0.866, CH.sub.3                                              (6) *6: S(-) configuration obtained by using hydrochloride salt of            S(-)[2-hydroxy-2-(3-methoxyphenyl)ethyl]amine {[α].sub.D.sup.19 =       -47.3° (C 0.87, CH.sub.3 OH)}-                                    

                                      TABLE 13                                    __________________________________________________________________________     ##STR484##                                                                   R.sup.1           Z              R.sup.2    Physical properties               __________________________________________________________________________     ##STR485##       NSO.sub.2 CH.sub.3                                                                            ##STR486##                                                                               ##STR487##                                                                   2.73 (3H, s, CH.sub.3),                                                       3.06-3.57                                                                      ##STR488##                                                                   7.20 (5H, s, benzene ring H                                                   × 5)                         ##STR489##       NSO.sub.2 CH.sub.3                                                                            ##STR490##                                                                               ##STR491##                                                                   2.80 (3H, s, CH.sub.3),                                                       3.09-3.64                                                                      ##STR492##                                                                   benzene ring H × 8)          ##STR493##                                                                                      ##STR494##                                                                                   ##STR495##                                                                               ##STR496##                                                                   2.33 (3H, s, CH.sub.3),                                                       3.03-3.62                                                                      ##STR497##                                                                   5.63 (1H, bs, OH), 6.50-7.82                                                   ##STR498##                                                                   H × 12), 8.77-9.85 (1H,                                                 b, OH)                             ##STR499##       NCN                                                                                           ##STR500##                                                                               ##STR501##                                                                    ##STR502##                                                                    ##STR503##                                                                    ##STR504##                                                                    ##STR505##                                                                    ##STR506##                                                                   6.6-7.5 (8H, m, benzene ring                                                  H × 8)                       ##STR507##       CHNO.sub.2                                                                                    ##STR508##                                                                               ##STR509##                                                                    ##STR510##                                                                   6.65-7.44 (6H, m, benzene                                                     ring                                                                          H × 4, thiophene ring H                                                 × 2),                                                                    ##STR511##                        ##STR512##       CHNO.sub.2                                                                                    ##STR513##                                                                               ##STR514##                                                                    ##STR515##                                                                   s, CH), 6.77-7.57 (9H, m,                                                     benzene ring H × 9)          ##STR516##       CHNO.sub.2                                                                                    ##STR517##                                                                              *Oily [α].sub.D.sup.23                                                  = +11.1° (C 1.00,                                                      chloroform)                        ##STR518##       CHNO.sub.2                                                                                    ##STR519##                                                                              **Oily [α].sub.D.sup.23                                                 = -10.7° (C 0.92,                                                      chloroform)                       __________________________________________________________________________     .sup.(1) *R(+) configuration obtained by using                                R(-)β-hydroxyphenethylamine                                              {[α].sub.D.sup.23 = -43.7° (C 2, ethanol) 97.5% optical          purity}.                                                                      .sup.2 **S(-) configuration obtained by using                                 S(+)β-hydroxyphenethylamine                                              {[ α].sub.D.sup.23 = +43.0° (C 2, ethanol) 96% optical           purity}.                                                                 

EXAMPLE 21

With 2 ml of ethanol was mixed 1 g of2-{[2-(dimethylamino)methyl-4-thiazolyl]methylthio}ethylamine and 1.1 gof 2-nitromethylene-5-phenyl-oxazolidine, and the resulting mixture wassubjected to reaction under reflux for 1 hour. After completion of thereaction, the reaction mixture was filtered with cooling, and thesolvent was removed by distillation under reduced pressure, after whichthe resulting residue was purified by a column chromatography (WakoSilica Gel C-200, eluent:chloroform:ethanol=20:1 by volume) to obtain1.3 g (yield 68%) ofN-{2-[[2-(dimethylamino)methyl-4-thiazolyl]methylthio]ethyl}-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediaminehaving a melting point of 100°-101° C.

NMR (CDCl₃) δ values: 2.20 (6H, s, --CH₃ ×2), 2.47-3.02 (2H, m, >CH₂),3.08-3.72 (4H, m, >CH₂ ×2), 3.60 (2H, s, >CH₂), 3.88 (2H, s, >CH₂), 4.87(1H, m, ##STR520## 6.63 (1H, s, ═CH--), 7.18 (1H, s, thiazole ring H),7.39 (5H, s, benzene ring H×5), 10.39 (1H, bs, >NH).

EXAMPLE 22

(1) With 2 ml of acetonitrile were mixed 1 g of2-{[2-(dimethylamino)methyl-4-thiazolyl]methylthio}ethylamine and 1.4 gof 1,1-bis(methylthio)-2-nitroethene, and the resulting mixture wassubjected to reaction under reflux for 2 hours. After completion of thereaction, the solvent was removed by distillation under reducedpressure, and 5 ml of ethanol was added to the resulting residue, afterwhich the insolubles were removed by filtration. The solvent was removedby distillation under reduced pressure, and the residue thus obtainedwas purified by a column chromatography (Wako Silica Gel C-200, eluent;chloroform:ethanol=20:1 by volume) to obtain 0.8 g (yield 53%) of oily1-{2-[[2-(dimethylamino)methyl-4-thiazolyl]methylthio]ethylamino}-1-methylthio-2-nitroethene.

NMR (CDCl₃) δ values: 2.36 (6H, s, --CH₃ ×2), 2.49 (3H, s, --CH₃),2.63-3.03 (2H, m, >CH₂), 3.45-3.84 (2H, m, >CH₂), 3.81 (2H, s, >CH₂),3.92 (2H, s, >CH₂), 6.67 (1H, s, ═CH--), 7.25 (1H, s, thiazole ring H),10.67 (1H, bs, >NH).

(2) In the same manner as in Example 2, 0.8 g of1-{2-[[2-(dimethylamino)methyl-4-thiazolyl]methylthio]ethylamino}-1-methylthio-2-nitroetheneobtained in above (1) and 0.4 g of DL-β-hydroxyphenethylamine werereacted and treated to obtain 0.7 g (yield 70%) ofN-{2-[[2-(dimethylamino)methyl-4-thiazolyl]methylthio]ethyl}-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediaminehaving a melting point of 100°-101° C.

EXAMPLE 23

(1) In the same manner as in Example 6-(2), 3.8 g of1-{[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]amino}-1-methylthio-2-nitroetheneand 2.6 g of2-{[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio}ethylaminewere reacted and treated to obtain 4.6 g (yield 87%) of oilyN-[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediamine.

The physical property (NMR) of this compound was identical with that inExample 7-(3).

(2) In the same manner as in Example 7-(4), 4.5 g ofN-[2-(tert.-butyl)dimethylsilyloxy-2-(3-methylphenyl)ethyl]-N'-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-2-nitro-1,1-ethenediaminewas reacted and treated to obtain 3.1 g (yield 79%) ofN-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-[2-hydroxy-2-(3-methylphenyl)ethyl]-2-nitro-1,1-ethenediaminehaving a melting point of 88°-89° C.

EXAMPLE 24

In the same manner as in Example 3 or 6, the corresponding startingmaterials were subjected to reaction, to obtain the objective compoundsshown in Tables 14, 15 and 16.

                  TABLE 14                                                        ______________________________________                                         ##STR521##                                                                   R.sup.2      R.sup.2       R.sup.2                                            ______________________________________                                         ##STR522##                                                                                 ##STR523##                                                                                  ##STR524##                                         ##STR525##                                                                                 ##STR526##                                                                                  ##STR527##                                         ##STR528##                                                                                 ##STR529##                                                                                  ##STR530##                                         ##STR531##                                                                                 ##STR532##                                                                                  ##STR533##                                         ##STR534##                                                                                 ##STR535##                                                                                  ##STR536##                                         ##STR537##                                                                                 ##STR538##                                                                                  ##STR539##                                         ##STR540##                                                                                 ##STR541##                                                                                  ##STR542##                                         ##STR543##                                                                                 ##STR544##                                                                                  ##STR545##                                         ##STR546##                                                                                 ##STR547##                                                                                  ##STR548##                                         ##STR549##                                                                                 ##STR550##                                                                                  ##STR551##                                         ##STR552##                                                                                 ##STR553##                                                                                  ##STR554##                                         ##STR555##                                                                                 ##STR556##                                                      ______________________________________                                    

The physical properties of these compounds were identical with those inExample 1.

                  TABLE 15                                                        ______________________________________                                         ##STR557##                                                                   R.sup.2    R.sup.2       R.sup.2                                              ______________________________________                                         ##STR558##                                                                               ##STR559##                                                                                  ##STR560##                                           ##STR561##                                                                               ##STR562##                                                                                  ##STR563##                                           ##STR564##                                                                               ##STR565##                                                                                  ##STR566##                                           ##STR567##                                                                               ##STR568##                                                                                  ##STR569##                                           ##STR570##                                                                               ##STR571##                                                                                  ##STR572##                                           ##STR573##                                                                               ##STR574##                                                                                  ##STR575##                                           ##STR576##                                                                               ##STR577##                                                                                  ##STR578##                                           ##STR579##                                                                               ##STR580##                                                                                  ##STR581##                                           ##STR582##                                                                               ##STR583##                                                                                  ##STR584##                                           ##STR585##                                                                               ##STR586##                                                                                  ##STR587##                                           ##STR588##                                                                               ##STR589##                                                        ______________________________________                                    

The physical properties of these compounds were identical with those inExample 2.

                  TABLE 16                                                        ______________________________________                                         ##STR590##                                                                   R.sup.2       R.sup.2       R.sup.2                                           ______________________________________                                         ##STR591##                                                                                  ##STR592##                                                                                  ##STR593##                                        ##STR594##                                                                                  ##STR595##                                                                                  ##STR596##                                        ##STR597##                                                                                  ##STR598##                                                                                  ##STR599##                                        ##STR600##                                                                                  ##STR601##                                                                                  ##STR602##                                        ##STR603##                                                                                  ##STR604##                                                                                  ##STR605##                                        ##STR606##                                                                                  ##STR607##                                                                                  ##STR608##                                        ##STR609##                                                                                  ##STR610##                                                                                  ##STR611##                                        ##STR612##                                                                                  ##STR613##                                                                                  ##STR614##                                        ##STR615##                                                                                  ##STR616##                                                                                  ##STR617##                                        ##STR618##                                                                                  ##STR619##                                                                                  ##STR620##                                        ##STR621##                                                                                  ##STR622##                                                                                  ##STR623##                                        ##STR624##                                                                   ______________________________________                                    

The physical properties of these compounds were identical with those inExample 10.

EXAMPLE 25

In the same manner as in Example 5, 7, 8 or 9, the correspondingstarting materials were subjected to reaction, to obtain the objectivecompounds shown in Tables 17 and 18.

                  TABLE 17                                                        ______________________________________                                         ##STR625##                                                                   R.sup.2     R.sup.2         R.sup.2                                           ______________________________________                                         ##STR626##                                                                                ##STR627##                                                                                    ##STR628##                                        ##STR629##                                                                                ##STR630##                                                                                    ##STR631##                                        ##STR632##                                                                                ##STR633##                                                                                    ##STR634##                                        ##STR635##                                                                                ##STR636##                                                                                    ##STR637##                                        ##STR638##                                                                                ##STR639##                                                                                    ##STR640##                                        ##STR641##                                                                                ##STR642##                                                                                    ##STR643##                                        ##STR644##                                                                                ##STR645##                                                                                    ##STR646##                                        ##STR647##                                                                                ##STR648##                                                                                    ##STR649##                                        ##STR650##                                                                                ##STR651##                                                                                    ##STR652##                                        ##STR653##                                                                                ##STR654##                                                                                    ##STR655##                                        ##STR656##                                                                                ##STR657##                                                                                    ##STR658##                                        ##STR659##                                                                                ##STR660##                                                       ______________________________________                                    

The physical properties of these compounds were identical with those inExample 1.

                  TABLE 18                                                        ______________________________________                                         ##STR661##                                                                   R.sup.2    R.sup.2       R.sup.2                                              ______________________________________                                         ##STR662##                                                                               ##STR663##                                                                                  ##STR664##                                           ##STR665##                                                                               ##STR666##                                                                                  ##STR667##                                           ##STR668##                                                                               ##STR669##                                                                                  ##STR670##                                           ##STR671##                                                                               ##STR672##                                                                                  ##STR673##                                           ##STR674##                                                                               ##STR675##                                                                                  ##STR676##                                           ##STR677##                                                                               ##STR678##                                                                                  ##STR679##                                           ##STR680##                                                                               ##STR681##                                                                                  ##STR682##                                           ##STR683##                                                                               ##STR684##                                                                                  ##STR685##                                           ##STR686##                                                                               ##STR687##                                                                                  ##STR688##                                           ##STR689##                                                                               ##STR690##                                                                                  ##STR691##                                           ##STR692##                                                                               ##STR693##                                                        ______________________________________                                    

The physical properties of these compounds were identical with those inExample 2.

PREPARATION EXAMPLE 1

    ______________________________________                                        N--[2-(4-fluorophenyl)-2-hydroxyethyl]-2-                                                                20      mg                                         nitro-N'.sup.1/8[3-(3-piperidinomethylphenoxy)-                               propyl]-1,1-ethenediamine (Drug No. 15)                                       Corn starch                25      mg                                         Crystalline cellulose      18      mg                                         Lactose                    100.7   mg                                         Magnesium stearate         1.3     mg                                         per tablet                 165     mg                                         ______________________________________                                    

Tablets were prepared with the above recipe by a conventional method.

PREPARATION EXAMPLE 2

    ______________________________________                                        N--{2-[[5-(dimethylamino)methyl-2-furyl]-                                                               20     mg                                           methylthio]ethyl}-N'--[2-hydroxy-2-(4-                                        hydroxyphenyl) ethyl]-2-nitro-1,1-                                            ethenediamine (Drug No. 3)                                                    Lactose                   278    mg                                           Corn starch               60     mg                                           Magnesium stearate        2      mg                                           per capsule               360    mg                                           ______________________________________                                    

Capsules were prepared with the above recipe by a conventional method.

PREPARATION EXAMPLE 3

As in Preparation Examples 1 and 2, tablets or capsules of each of DrugNos. 4, 22, 29 and 32 were prepared.

What is claimed is:
 1. A compound of the formula: ##STR694## wherein R²is phenyl, indanyl, thienyl, furyl or pyridyl which may optionally besubstituted by at least one substituent selected from the groupconsisting of halogen, hydroxyl, nitro, amino, hydroxy-C₁₋₄ -alkyl,cyano, C₁₋₈ -alkyl, C₁₋₄ -alkoxy, C₁₋₄ -alkythio, C₁₋₄ -alkylsulfinyl,C₁₋₄ -alkylsulfonyl, halogeno-C₁₋₄ alkyl, di-C₁₋₄ -alkylamino,carbamoyl, C₂₋₅ -alkanoyl, or methylenedioxy in which the oxygen atomsare linked to the adjacent carbon atoms;R³ is hydrogen or a hydroxylprotecting group selected from the group consisting of formyl, C₂ -C₅alkanoyl, C₅ -C₈ cycloalkanecarbonyl, benzoyl, toluoyl, 2-naphthoyl,2-thenoyl, 3-furoyl, nicotinoyl, 1,1-dimethylpropoxycarbonyl,t-butoxycarbonyl, isopropoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,ethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,4-(phenylazo)benzyloxycarbonyl,4-(4-methoxypphenylazo)benzyloxycarbonyl, monochloroacetyl,trifluoroacetyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl,8-quinolyloxycarbonyl, benzyl, diphenylmethyl, trityl, C₁₋₈ alkyl,methoxymethyl, tetrahydrofuryl, tetrahydropyranyl, 2-nitrophenylthio,2,4-dinitrophenylthio, trimethylsilyl and t-butyldimethylsilyl; Y isC₁₋₄ alkylene; Z is oxygen; sulfur; or NR⁴, wherein R⁴ is formyl, C₂₋₅alkanoyl, C₅₋₈ cycloalkanecarbonyl, benzoyl, toluoyl, 2-naphthoyl,2-thenoyl, 3-furoyl, nicotinoyl, phenyl, naphthyl, indanyl,benzenesulfonyl, naphthalenesulfonyl, phenyloxy, naphthyloxy,formylamino, C₂₋₅ alkanoylamino, C₅₋₈ cycloalkanecarbonylamino,benzoylamino, toluoylamino, 2-naphthoylamino, 2-thenoylamino,3-furoylamino, nicotinoylamino, each of which may optionally besubstituted by at least one substituent selected from the groupconsisting of C₁₋₈ -alkyl, halogeno-C₁₋₄ -alkyl, C₁₋₄ -alkoxy andhalogen; or hydrogen; cyano; hydroxyl, nitro; C₁₋₈ -alkyl; C₂₋₄-alkenyl; C₁₋₄ -alkoxy; carbamoyl; sulfamoyl; C₁₋₄ -alkoxycarbonyl, C₁₋₄-alkylsulfonyl, C₁₋₄ -alkoxycarbonylamino, or carboxy C₁₋₄ -alkylamino;or CHR⁵, wherein R⁵ is formyl, C₂₋₅ -alkanoyl, C₅₋₈-cycloalkanecarbonyl, benzoyl, toluoyl, 2-naphthoyl, 2-thenoyl,3-furoyl, nicotinoyl, phenyl, naphthyl, indanyl, benzenesulfonyl, ornaphthalenesulfonyl, which may optionally be substituted by at least onesubstituent selected from the group consisting of C₁₋₈ -alkyl,halogenoC₁₋₄ -alkyl, C₁₋₄ -alkoxy and halogen or C₁₋₄ -alkylsulfonyl ornitro; and U is halogen, C₁₋₄ -alkylthio, C₁₋₄ -alkysulfinyl,benzylthio, C₁₋₄ -alkoxy, 1-imidazolyl, 3,5-dimethylpyrazolyl, or anethyleneimino group.
 2. The compound according to claim 1, wherein Z isNR⁴, wherein R⁴ is cyano or C₁₋₄ -alkylsulfonyl, or CHR⁵, wherein R⁵ isnitro.
 3. The compound according to claim 1, wherein U is an alkylthiogroup.
 4. The compound according to claim 1, wherein U is anethyleneimino group.
 5. The compound according to claim 1, 3 or 4,wherein Z is a nitromethylene group.
 6. The compound according to claim1, 3 or 4, wherein Y is a methylene group.
 7. A compound of the formula:##STR695## wherein R² is phenyl, indanyl, thienyl, furyl or pyridylwhich may optionally be substituted by at least one substituent selectedfrom the group consisting of halogen, hydroxyl, nitro, amino, hydroxyC₁₋₄ -alkyl, cyano, C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, halogeno-C₁₋₄ alkyl, di-C₁₋₄alkylamino, carbamoyl, C₂₋₅ alkanoyl, or methylenedioxy in which theoxygen atoms are linked to the adjacent carbon atoms; R³ is hydrogen ora hydroxyl protecting group selected from the group consisting offormyl, C₂ -C₅ alkanoyl, C₅ -C₈ cycloalkanecarbonyl, benzoyl, toluoyl,2-naphthoyl, 2-thenoyl, 3-furoyl, nicotinoyl,1,1-dimethylpropoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl,2,2,2-trichloroethoxycarbonyl, ethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 4-(4-methoxyphenylazo)benzyloxycarbonyl,monochloroacetyl, trifluoroacetyl, 2-furfuryloxycarbonyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl diphenylmethyl,trityl, C₁₋₈ alkyl, methoxymethyl, tetrahydrofuryl, tetrahydropyranyl,2-nitrophenylthio, 2,4-dinitrophenylthio, trimethylsilyl andt-butyldimethylsilyl; Y is C₁₋₄ alkylene; U is C₁₋₄ -alkylthio or anethyleneimino group.
 8. The compound of claim 7, wherein said Usubstituent is C₁₋₄ -alkylthio. 9.1-{[2-Hydroxy-2-(3-methylphenyl)ethyl]amino}-1-methylthio-2-nitroethene.10.1-Aziridino-1-{[2-(tert-butyl)dimethylsiloxy-2-(3-methylphenyl)ethyl]amino}-2-nitroethene.